Controlled absorption water-soluble pharmaceutically active organic compound formulation for once-daily administration

ABSTRACT

The present disclosure provides a once-daily water-soluble pharmaceutically active formulation for oral administration. In certain embodiments, the composition comprises a watersoluble pharmaceutically active organic compound incorporated into a small particulate, each particulate having a core of the water-soluble pharmaceutically active organic compound or an acceptable salt thereof in reversible association with a pharmaceutically acceptable drug-binding polymer. The core of the composition being surrounded by an insoluble water permeable membrane that is capable of delaying the dissolution of the pharmaceutically active compound therewithin and providing for extended release of the pharmaceutically active compound. In some embodiments, the formulation of the invention are designed to extend release of the pharmaceutically active organic compound for about 3 hours to about 8 hours, thereby enabling preparation of an extended release formulation for any pharmaceutically active compound with a half-life of from about 16 hours to about 21 hours.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present U.S. patent application is a continuation of U.S. patentapplication Ser. No. 14/119,387 filed 24 Feb. 2014, is a U.S. NationalStage application of international application number PCT/US2012/041331filed 7 Jun. 2012, which claims priority to U.S. Provisional PatentApplication No. 61/494,659 filed 8 Jun. 2011, all of which areincorporated herein by reference in their entireties.

FIELD OF THE INVENTION

This invention relates to a controlled absorption pharmaceuticalformulation and, in particular, to a controlled absorption form ofpharmaceutically active compounds for oral administration in an easy toswallow particulate formulation suitable for use with an acceptable‘soft food’ for those with difficulty in swallowing a tablet, capsule orpill and for administration of pharmaceutically active compounds in agastro-nasal feeding tube or other “feeding tube” type apparatus wheretimed release of the active is desired.

BACKGROUND OF THE INVENTION

Many drugs that are water soluble and easily absorbed from thegastrointestinal track could be more advantageously formulated ascontrolled release once daily oral dosage forms instead of as immediaterelease dosage forms. Since a standard immediate release formulation isone that is designed to release the drug immediately upon dissolution inthe gastrointestinal tract, there are at least two reasons why, theswitch to controlled release dosage forms would be beneficial. First,pertaining particularly to oral delivery, drugs ingested are passedthrough the gastrointestinal tract within 24 hours and sometimes in afew hours after ingestion. Second, pertaining to oral and parenteraldelivery, the half life of most drugs is less than a day and usually nomore than a few hours. Thus, it is very difficult for a standardimmediate release single oral dose of a drug to be effective for morethan 24 hours and in most cases more than several hours.

Naproxen, for example, is a propionic acid derivative((S)-6-methoxy-methyl-2-naphthaleneacetic acid), non-steroidal,anti-inflammatory drug (NSAID) that exhibits analgesic and antipyreticproperties. Naproxen represents pharmaceutically active compounds which(a) are water soluble and easily absorbed from the gastrointestinaltrack; (a) would be advantageous to be administered once a day insteadof multiple times a day; and (c) are administered to a wide range ofpatients where an analgesic effect due to the inhibition of inflammationis desired. Many of the effects of naproxen are associated with theinhibition of prostaglandin synthesis and in particular cyclo-oxygenase(COX), a family of enzymes (COX 1 and COX 2 seem to currently be themost medically important), that catalyze the formation of prostaglandinprecursors from arachidonic acid (Simmons, D. L. et al., Pharmacol. Rev.2004, 56, pp. 387-437). Inhibition of COX 2 is believed to be effectivein blocking the arachidonic acid metabolic pathway that is mostresponsible for pain and inflammation. Naproxen is used to relieve mildto moderately severe pain in rheumatoid arthritis, osteoarthritis andother inflammatory conditions.

Plasma naproxen concentrations of 30-90 μg/mL are reportedly requiredfor anti-inflammatory or analgesic effects. Plasma naproxen levelsbetween 30-70 μg/mL (Sevelius, H. et al., Br. J. Clin. Pharmacol. 1980,10, pp. 259-263) have been reported to reduce post partum pain. Pain inpatients with rheumatoid arthritis suggested that pain reduction in thiscondition occurred at plasma naproxen levels above 50 μg/mL (Day, R. O.et al., Clin. Pharmacol, Ther. 1982, 31, pp. 733-740). Thus, while therate of absorption may affect the onset of analgesic activity, continuedplasma levels of the drug are likely to be important in maintaininganalgesia.

Examples of extended release formulations aimed at slowing release ofdrug as it travels through the gastrointestinal tract include thosedeveloped by Elan, Depomed, Alza, Biovail, Pennwest and KosPharmaceuticals. These drug delivery systems are based on polymercoatings, hydrogels, polymer foams, osmotic pressure, and othertechnologies (for a review, see, Rosen, H. & T. Arbribat, 2005, Nat.Rev. Drug Discovery, published online Apr. 22, 2005,doi:10.1038/nrd1721). Other research has focused on the development ofprodrugs designed to improve physicochemical, biopharmaceutical orpharmokinetic properties of drugs, including controlling or extendingdrug release in the body (for a review, see J. Rautio, et al., 2008,Nat. Rev. Drug Discovery Volume 7, March 2008, 255-270).

Notwithstanding the technical advances referred to above, a single doseof an immediate or extended release orally delivered formulation of adrug is almost never effective for at least a day, save a handful ofdrugs that have very long half lives. Thus, there is a need in the artto develop drug compositions and methods of manufacture that are able toextend the delivery of a single drug dose to beyond one day, andpreferably to multiple days. This invention addresses those needs.

BRIEF SUMMARY OF THE INVENTION

In one aspect, the present disclosure provides a particulatecomposition. In certain embodiments the particulate compositioncomprises (a) a core, said core comprising a pharmaceutically activesubstance, said pharmaceutically active substance having an interactionwith said set of one or more drug binding polymers having; and (b) acoat, said coat comprising a membrane-forming polymer, saidmembrane-forming polymer surrounding said core, wherein saidpharmaceutically active substance comprises a pharmaceutically activecompound, a pharmaceutically acceptable salt, of said pharmaceuticallyactive compound or a combination thereof. In some embodiments, theparticulate composition comprises (a) an inert core, said inert corecomprising a Set of one or more drug binding polymers; and (b) a coat,said coat comprising a membrane-forming polymer, said membrane-formingpolymer surrounding said core.

In one embodiment, the set of one or more drug binding polymers isselected from the group consisting of ethylcellulose, cellulose acetate,cellulose propionate (lower, medium or higher molecular weight),cellulose acetate propionate, cellulose acetate butyrate, celluloseacetate phthalate, cellulose triacetate, poly(methyl methacrylate),poly(ethyl methacrylate), poly(butyl methacrylate), poly(isobutylmethacrylate), poly(hexyl methacrylate), poly(isodecyl methacrylate),poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methylacrylate), poly(isopropyl acrylate), poly(isobutyl acrylate),poly(octadecyl acrylate), poly (ethylene), poly(ethylene) low density,poly(ethylene) high density, poly(propylene), poly(ethylene oxide),poly(ethylene terephthalate), poly(vinyl isobutyl ether), poly(vinylacetate), poly(vinyl chloride) or polyurethane and combinations thereof.

In another embodiment, the pharmaceutically active substance and the setof one or more drug binding polymers respectively are present in thecore particle in a weight ratio of from about 20:1 to about 1:2(pharmaceutically active substance: drug binding polymer(s)). In yetanother embodiment, the interaction between said pharmaceutically activesubstance and said set of one or more drug binding polymers compriseschemical bonding, ionic bonding, complexation, van der Waalsinteraction, hydrogen bonding, or combinations thereof. In anotherembodiment, at least one of the set of one or more drug binding polymersis insoluble in water. In yet another embodiment, at least one of theset of One or more drug binding polymers is soluble in water. In afurther embodiment, the coat comprises a water-insoluble,water-permeable polymer capable of retarding drug release.

In one embodiment, the core comprises a powder, the powder comprisingparticles of the pharmaceutically active substance mixed with particlesof the set of one or more drug binding polymers, and wherein the coatcomprises a water-insoluble, water-permeable polymer. In a furtherembodiment, the core comprises a powder, the powder comprising particlesof the pharmaceutically, active substance mixed with particles of theset of one or more drug binding polymers, wherein the set of one or moredrug binding polymers comprise at least one pharmaceutically acceptablewater insoluble polymer, and wherein the coat comprises awater-insoluble, water-permeable polymer.

In another embodiment, a particulate composition according with thepresent invention comprises microparticles/microparticulates havingaverage diameter of from about 100 μm to about 900 μm.

In another aspect, the present disclosure provides a method of making aparticulate composition. In certain embodiments, the method comprises(a) blending a powder, the powder comprising particles of apharmaceutically active substance and particles of a set of one or morepolymers, to form a homogenous powder blend; (b) shaping a portion ofthe homogenous powder blend to form a central core; and (c) applying apolymer binding solution to the central core to form a layered structureon the central core. In an embodiment, the pharmaceutically activesubstance comprises a pharmaceutically active compound, apharmaceutically acceptable salt of the pharmaceutically active compoundor a combination thereof.

In one embodiment, the method of making a particulate compositioncomprises (a) blending a powder, the powder comprising particles of aset of one or more polymers, to form a homogenous powder blend; (b)shaping a portion of the homogenous powder blend to form a central inertcore; and (c) applying a polymer binding solution to the central inertcore, to form a layered structure on the central inert core.

In yet another aspect, the present disclosure provides an oralpharmaceutical sustained release composition. In some embodiments, theoral pharmaceutical sustained release composition comprises theparticulate composition in accordance with the present invention. In afurther embodiment, the oral pharmaceutical sustained releasecomposition has a dissolution rate which when measured in a type Idissolution basket apparatus according to U.S. Pharmacopoeia XXII inphosphate buffer at pH 7.2 and at 75 r.p.m. corresponds to the followingdissolution pattern:

(a) from 15 to 30% of the total pharmaceutically active, chemical isreleased after 0.5 hours of measurement in said apparatus;

(b) from 25 to 60% of the total pharmaceutically active chemical isreleased after 1 hour of measurement in said apparatus; and

(c) not less than 65% of the total pharmaceutically active chemical isreleased after 4 hours of measurement in said apparatus.

In an embodiment, a pharmaceutical formulation in accordance with thepresent invention comprises a microparticulate composition as describedherein filled into capsules or compressed into tablets. In anotherembodiment, a pharmaceutical formulation in accordance with the presentinvention comprises a microparticulate composition as described hereinfilled into capsules. In another embodiment, a pharmaceuticalformulation in accordance with the present invention comprises amicroparticulate composition as described herein compressed intotablets. In another embodiment, said capsules or said tablets rapidlydissolve in any aqueous medium to release microparticulates of saidparticulate composition. In yet another embodiment, a pharmaceuticallyactive substance contained in said particulate composition is releasedin a controlled manner. In another embodiment, said pharmaceuticallyactive substance is released in a controlled manner having a releaseprofile that is substantially the same/identical to the release profileof said microparticulates alone.

In another aspect, the present disclosure provides a method forextending delivery of a single dose of a pharmaceutically activesubstance to once daily or to beyond one day from administration of thedose to a subject. In an embodiment, the method for extending deliveryof a single dose of a pharmaceutically active substance comprises (a)blending powder particles of the pharmaceutically active substance withpowder particles of a set done or more polymers to form a homogenouspowder blend, wherein the a pharmaceutically active substance comprisesa pharmaceutically active compound, a pharmaceutically acceptable saltof the pharmaceutically active compound or a combination thereof; (b)shaping a portion of the homogenous powder blend to form a central core;and (c) applying a polymer binding solution to the central core to forma layered structure on the central core to form a pharmaceuticalcomposition, wherein the pharmaceutical composition delivers thepharmaceutically active, substance to the subject for at least one ormore days from administration of a single dose of the pharmaceuticalcomposition.

Other features and advantages of the invention will be understood byreference to the drawings, detailed description and examples thatfollow.

BRIEF DESCRIPTION OF DRAWINGS

The foregoing summary, as well as the following detailed description ofembodiments of the particulate composition, methods of making and usingthe composition, and controlled release pharmaceutical composition forcontrolled delivery of drugs, will be better understood when read inconjunction with the appended drawings of exemplary embodiments. Itshould be understood, however, that the invention is not limited to theprecise arrangements and instrumentalities shown.

In the drawings:

FIG. 1 is a graph illustrating percent naproxen released from aformulation in accordance with exemplary Formulation 1, described in theExamples Section, when tested by the method of the U.S. PharmacopaeiaXXII Basket method in phosphate buffer at pH 7.2 and at 75 r.p.m. versustime (hours);

FIG. 2 is a graph illustrating percent naproxen released from aformulation in accordance with exemplary Formulation 2, described in theExamples Section, when tested by the method of the U.S. PharmacopaeiaXXII Basket method in phosphate buffer at pH 7.2 and at 75 r.p.m. versustime (hours);

FIG. 3 is a graph illustrating percent naproxen released from aformulation in accordance with exemplary Formulation 3, described in theExamples Section, when tested by the method of the U.S. PharmacopaeiaXXII Basket method in phosphate buffer at pH 7.2 and at 75 r.p.m. versustime (hours);

FIG. 4 is a graph illustrating percent naproxen released from aformulation in accordance with exemplary Formulation 4, described in theExamples Section, when tested by the method of the U.S. PharmacopaeiaXXII Basket method in phosphate buffer at pH 7.2 and at 75 r.p.m. versustime (hours);

FIG. 5 is a graph illustrating percent naproxen released from aformulation in accordance with formulation 5, described in the ExamplesSection, when tested by the method of the U.S. Pharmacopaeia XXII Basketmethod in phosphate buffer at pH 7.2 and at 75 r.p.m. versus time(hours);

FIG. 6 illustrates particle size distribution for Formulation 2; and

FIG. 7 illustrates particle distribution for Formulation 4.

DETAILED DESCRIPTION OF THE INVENTION

All references, including publications, patent applications, andpatents, cited herein are hereby incorporated by reference to the sameextent as, if each reference were individually and specificallyindicated to be incorporated by reference and were set forth in itsentirety herein.

As used herein, the terms “drug,” “biologically active substance,” andthe like, are used interchangeably herein to refer to a substance, or acomposition containing one or more substances; having a biologicalactivity or therapeutic effect in a human or animal.

Half life is defined as the time that it takes for 50% of the dosageabsorbed into the body to be excreted from the body.

The terms “patient,” “subject” or “individual” are used interchangeablyherein and refer to a human or an animal that is the object, oftreatment, observation or experiment, inasmuch as the present inventionis contemplated to have utility in human and veterinary medicine.

A single dose or single administration is defined as the dose of a drugthat is delivered at approximately the same time and can be composed ofone or more capsules or tablets, liquids, powders, dispersions, and thelike.

As used herein, a “therapeutically effective amount” or an “effectiveamount” or an “efficacious amount” is the amount of a substance orcomposition sufficient to provide a beneficial effect to the individualto whom the substance or composition is administered.

The use of the terms “a” and “an” and “the” and similar referents in thecontext of describing the invention (especially in the context of thefollowing claims) are to be construed to cover both the singular and theplural, unless otherwise indicated herein or clearly contradicted bycontext. The terms “comprising,” “having,” “including,” and “containing”are to be construed as open-ended terms (i.e., meaning “including, butnot limited to,”) unless otherwise noted. Recitation of ranges of valuesherein are merely intended to serve as a shorthand method of referringindividually to each separate value falling within the range, unlessotherwise indicated, herein, and each separate value is incorporatedinto the specification as if it were individually recited herein. Allmethods described herein can be performed in any suitable order unlessotherwise indicated herein or otherwise clearly contradicted by context.The use of any and all examples, or exemplary language (e.g., “such as”)provided herein, is intended merely to better illuminate the inventionand does not pose a limitation on the scope of the invention unlessotherwise claimed. No language in the specification should be construedas indicating any non-claimed element as essential to the practice ofthe invention.

A. Biologically Active Compounds

Suitable biologically active substances that can be used with themethods and compositions of the present invention can be of any class ofsubstances, including anesthetics, antidiabetic, bone metabolicmodulators, cardiovascular agents, central nervous system depressants,gastrointestinal agents, antibiotics, antivirals, antiinfectives,antibacterials, antineoplastics, hormones, steroid agents,antiparkensonian, contraceptive, erectile dysfunction agents,analgesics, pain medications, anti-inflammatories, antilipidemic agents,diagnostic agents, antihistamines, peptide and proteins, urinary tractagents, psychotherapeutics, osteoporosis medications, immunomodulatorsand antiasthmatics.

Non-limiting examples of suitable pharmaceutically active substances foruse with the methods and compositions include abacavir, abamectin,abanoquil, abaperidone, abarelix, abecamil, abiraterone, abitesartan,ablukast, abunidazole, acadesine, acamprosate, acaprazine, acebrochol,acebutolol, acecamide, acecarbromal, aceclidine, aceclofenac,acedapsone, acediasulfone, acedoben, acefluranol, acefurtiamine,acefylline clofibrol, acefylline piperazine, aceglatone, aceglutaminde,acemetacin, aceneuramic acid, acenocoumarol, acepeprone, acepromazine,aceprometazine, acequinoline, acesulfame, acetaminosalol, acetanilide,acetarsone, acetaminophen, acetazolamide, acetiamine, acetiromate,acetohexamide, acetophenazone, acetophenetidin, acetorphine,acetosulfone, acetriozoic acid, acetylcysteine, acetyldigitoxin,acetylleucine, acetyltributyl citrate, acetyltriethyl citrate,acevaltrate, acexamin acid, acifran, acipimox, acitazanolast, acitemate,acitretin, acivicin, alcantate, aclarubicin, aclatonium napadisilate,acolbifene, aconiazide, aconitine, acotiamide, acoxatrine, acreozast,acridorex, acriflavine, acrihellin, acrisorcin, acrivastine,acroinonide, acronine, actaplanin, actarit, actinoquinol, actisolide,actodigin, acyclovir, adafenoxate, adamexine, adapalene, adaprolol,adatanserin, adefovir, adekalant, adelmidrol, ademitionine, adenosine,adibendal, adicillin, adimolol, adinazolam, adiphenine, aditeren,aditoprim, adosopine, adozelesin, adrafinil, adrenalone, adrogolide,afalanine, afeletecan, afloqualone, afovirsen, afurolol, aganodine,aglepristone, agomelatine, aklomide, alacepril, alafosfalin, alagebrium,alamecin, alamifovir, alanine, alanosine, alaproclate, alatrofloxacin,alazanine triclofenate, albaconazole, albendazole, albuterol, albutoin,alclofenac, alclometasone, alcloxa, alcuronium, aldioxa, aldosterone,alemcinal, alendronic acid, alentemol, alepride, alestramustine,aletamine, alexidine, alexitol, alexomycin, alfacalcidol, alfadex,alfidalone, alfaprostol, alfatradiol, aldaxalone, alfentranil,alfluzosin, algeidrate, algestone, alibendol, aliconazole, alifedrine,alifurane, alilusem, alimadol, alinastine, alinidine, alipaminde,aliskiren, alitame, alitretinoin, alizapride, alletorphine,allobarbitol, allocamide, allocupreide, allomethadione, allopurinol,allylestrenol, allylprodine, almecillin, almestrone, alminoprofen,almitrine, almokalant, almotriptan, almoxatone, almurtide, alnespirone,alniditan, alonacic, acid, alonimid, aloracetam, alosetron, alovudine,aloxidone, aloxiprin, aloxistatin, alozafone, alpertine, alphameprodine,alphamethadol, alphamethyldopa, alphaprodine, alpidem, alpiropride,alprafenone, alprazolam, alprenolol, alprenoxitne, alprostadil,alrestatin, altanseriti, altapizone, alteconazole, althiazide,altinicline, altoqualiine, altrenogast, altretamine, alvemeline,alverine, alvimopan, alvocidib, amadinone, amafalone, amanozine,amantadine, amantocillin, ambamustine, ambasilide, ambazone, ambenonium,ambenoxan, ambomycin, ambrisentan, ambroxol, ambruticin, ambucaine,ambucetamide, ambuphylline, ambuside, ambutonium, amcinafal, amcinafide,amcinonide, amdinocillin, amdoxovir, ambucort, amedalin, amelometasone,ameltolide, amelubant, amesergide, ametantrone, amethocaine, amezapine,ameziniurn, amfenac, amfepentorex, amfetaminil, amflutizole, amfonelic,amicarbalide, amicloral, amicycline, anidantel, amidapsone, amidephrine,amiflamine, amifloverine, amifloxacin, amifostine, amiglumide, amikacin,amikhelline, amiloride, amiloxate, aminacrine, amindocate, amineptine,amiriciglutethimide, aminohippuric acid, aminolevulinic acid,aminometradine, aminopentamide, aminophenazone, aminophylline,aminopromazine, aminopterin, aminopyrine, aminoquinol, aminoquinuride,aminorex, aminosalicylic acid, aminothiazole, amiodarone, amiperone,amphenazole, amipizone, amiprolose, amiquinsin, aminometradine,amisulprode, amiterol, amithiozone, amitivir, amitraz, amitriptyline,amitriptyinoxide, amixetrine, amlexanox, amlintide, amlodipine,amocarzine, amodiaquine, amolanone, amonafide, amoproxan, amopyroquine,amorolfine, amoscanate, amosulatol, amotosalen, amotriphene, amoxapine,amoxecaine, amoxicillin, amoxydramine, amperozide, anphechloral,amphenidone, amphetamine, amphomycin, amphotalide, amphotericin,ampicillin, ampiroxicam, amprenavir, amprolium, ampyrimine, ampyzine,amquinate, amrubicin, amsacrine, amtolmetin, amustaline, amylobarbital,angestone, anagrelide, anakinra, anaritide, anastrozole, anatibant,anaxirone, anazocine, anazolene, ancarolol, ancitabine, andolast,androstenediol, androstenedione, andulafungin, anecortave,anetholtrithion, angiotensin amide, andidoxamine, anidulafungin,anilamate, anileridine, anilopam, anipamil, aniracetam, anirolate,anisacril, anisindione, anisopirol, anisotropine, anisperimus,anitrazafen, anpirtoline, ansoxetine, antafenite, antazoline,antazonite, anthelmycin, anthralin, anthramycin, antipyrine,antrafenine, apadoline, apafant, apalcillin, apaxafylline, apaziquone,apazone, apicycline, aplindore, apomorphine, apovincamine,apraclonidine, apramycin, aprepitant, aprakalim, aprindine,aprinocarsine, apofene, aprosulate, aptazapine, aptiganel, aptocaine,aranidipine, aranotin, arbaprosil, arbekacin, arbutamine, arclofenin,ardacin, ardeparin, arecoline, arfalasin, arfendazam, arformoterol,argatroban, argimesna, argipressin, argiprestocin, arlidone,arimoclomol, aripiprazole, armodafinil, arnolol, arofylline, artinolol,arprinocid, arpromidine, arsangic acid, arteflene, artemether,artemisinin, artemotil, artenimol, artesunate, articaine, anilide,arundic acid, arzoxifene, ascorbic acid, arsenapine, aseripide,asimadoline, asobamast, asocainol, asoprisnil, aspartame, aspartocin,asperlin, aspirin, aspoxicillin, astemizole, astromicin, asulacrine,atamestane, ataprost, ataquimast, atavanavir, atenolol, atevirdine,atibeprone, atilmotin, atipamegole, atipromod, atiprosin, atizoram,atliprofen, atocalcitol, atolide, atomoxetine, atorvastatin, atosiban,atovaquone, atracurium, atrasentan, atraleuton, atrimustine,atrinositol, atromepane, atropine, atropine oxide, auranofin,aurothioglucose, avanafil, avasimibe, avicatonin, avalamycin, aviptadil,avitriptan, avizafone, avobenzone, azoparcin, avorelin, pyridine,axamozide, axitirome, axomadol, azabon, azabuperone, azacitidine,azacitidine, azaclorzine, azaconazole, azacosrterol, azacyclonol,azaftozine, azalanstat, azalomycin, azaloxan, azamethiphos,azamethonium, azamulin, azanator, azanidazole, azaperone, azapetine,azaquinzole, azaribine, azarole, azaserine, azasetron, azaspirium,azastene, azatadine, azathioprine, azelaic acid, azelastine,azelinnidipine, azepexole, azepindole, azetepa, azetirelin,azidamfenicol, azidocillin, azimexon, azimilide, azintamide, azipramide,azithromycin, azlocillin, azlocillin, azolimine, azosemide, aztomycin,aztreonam, azumolene, bactunpicillin, bacitracin, baclofen,bacmecillinam, bakeprofen, balaglitazone, balazipone, balofloxacin,balsalazide, bamaluzole, bamaquimast, bambermycin, bambuterol, bamethan,bamifylline, bamipine, bamirastine, bamidazole, banoxantrone,baquiloprim, barbexaclone, barbital, barixibat, barmastine, barnidipine,barucamide, bantsiban, basifungin, batalbulin, batanopride, batebulast,batelapine, batilol, batimastat, batoprozine, baxitoizine, bazedoxifene,bazinaprine, becanthone, becatecarin, beciparcil, beclamide,becliconazole, beclobrate, beclomethasone, beclotiamine, befetupitant,befiperide, befloxatone, befunolol, befuraline, bekanamycin,belapericlone, belarizine, belfosdil, belotecan, beloxamide, beloxepin,bemarinone, bemegride, bemesetron, bemetizide, beminafil, bemiparin,bemetradine, bemoradan, bemotrizinol, benactyzine, benafentrine,benapryzine, benaxibine, benazepril, bencianol, bencisteine,benclonidine, bencyclane, bendacalpl, bendamustine, bendazac, bendazol,benderizine, bendroflumethazide, benethamine penicillin, benexate,benfluorex, benfosfonnin, benfotiamine, benfluorodil, benhepazone,benidipine, benthoxin, benolizime, benorilate, benorterone, benoxifos,benoxaprofen, benoxinate, benpenolisin, benperidol, benproperine,benrixate, bensalan, benserazide, bensuldazic acid, bentazepam,bentemazole, bentiamine, bentipimine, bentiromide, bentoquatam,benurestat, benzalkonium, benzarone, benzbromarone, benzestrol,benzethidine, benzethonium, benzetirrride, benzilonium, benzindopyrine,benziodarone, benzmalecene, benznidazole, benzobarbital, benzocaine,benzoclidine, benzoctamine, benzodepa, benzododecinium, benzonatate,benzopyrronium, benzoquinonium, benzotript, benzoxiquine, benzoxonium,benzoylpas, benzphetamine, benzpiperylon, benzpyrinium, benzquercin,benzquinamide, benzthiazide, benztropine, benzydamine,benzylhydrochlorothiazide, benzylpenicillin, benzylsulfamide, bepafant,beperidium, bephenium, bepiastine, bepridil, beractant, beraprost,berberine, berefrine, bergenin, berlafenone, bermoprofen, bertosamil,berupipam, bervastatin, berythromycin, besigomsin, besipirdine,besonprodil, besulpamide, besunide, beta carotene, betacetylmethaclol,betahistine, betaine, betameprodine, betamethadol, betamethasone,betamicin, betamipron, betaprodine, betaxolol, betazole, bethanacol,bethanidine, betiatide, betoxycaine, bevantolol, bevonium, bexarotene,bexlosteride, bezafibrate, beztiramide, bialamicol, biapenem,bibezonium, bibrocathol, bilcalutamide, bicifadine, bicoldil,biclofibrate, biclotymol, bicozamycin, bidimazium, bidisomide,bietamiverine, bietaserpine, bifemelane, bifepramide, bifeprofen,bifeprunox, bifluranol, bifonazole, bilastine, bimakalim, bimatoprost,bimoclomol, bimosiamose, bindarit, binedaline, binfioxacin, binfibrate,biniramycin, binizolast, binodenosine, binospirone, bioallethrin, botin,bipenamol, biperiden, bipheruunine, biricodar, biriperone, bisacodyl,bisantrene, bisaramil, bisbendazole, bisbentiamine, bisbutiamine,bisdequilinium, bisfenazone, bisfentidine, bisnafide, bisorbin,bisoctriazole, bisoprolol, bisorcic, bisoxatin, bispyrithione, bithonol,bithionoloxide, butipazone, bitolterol, bitoscanate, bivalirudin,bizelesin, bleomycin, blonanserine, bluensomycin, bofumustine,bolandiol, bolasterone, bolazine, boldenone, bolenol, bolmantalate,bometolol, bopindolol, bomaprine, bornaprolol, borelone, borocaptane,bortezomib, bosentan, botiacrine, boxidine, brallobarbital,brasofensine, brazergoline, brefonalol, bremazocine, brequinar,bretazenil, bretyllium, brifentanil, brimonidine, brinazaprone,brindoxime, brinzolamide, brivudine, brobactam, broclepride,brocrestine, brocrinat, brodimoprim, brofaromine, brofoxine,brolaconazole, brolamfetamine, bromadoline, bromamid, bromazepam,bromchlorenone, bromebric acid, bromerguride, brometenamine, bromfenac,bromhexene, bomindione, bromisoyalum, bromociclen, bromocriptine,bromodiphenylhydrantine, bromofenfos, bromofos, bromopride, bromoxanide,bromperidol, brompheniramine, broparestrol, broperamol, bropirimine,broquinaldol, brosotaminde, brostallicin, brosuxithide, brotianide,brotizolam, brovanexine, brovincamine, braxaldine, broxaterol,broxitalamide, broxuridine, broxyquinoline, bucamide, bucetin,buciclovir, bucillamine, bucindolol, bucladesine, buclizine,buclosaminde, bucloxic acid, bucolme, bucricaine, bucromarone,bucumolol, budesonide, budipine, budotitane budralazine, bufenadrine,bufeniode, bufetolol, bufexamac, bufezolac, bufromedil, bufogentin,buformin, bufrolin, bufuralal, bufylline, bulaquine, bumadizone,bumecaine, bumepidil, bumetanide, bumetriazole, bunaftine, bunamidine,bunamiodyl, bunaprolast, bunazosin, bunitrolol, bunolol, buparvaquone,bupicomide, bupivacaine, bupranolol, buprenorphine, bupropion,buquinerin, buquirfolate, buquitetine, buramate, burodiline, buserelin,buspirone, busulfan, butobarbital, butacaine, butacetin, butaclamol,butadiazamide, butafasfan, butalamine, butalbital, butamben, butamirate,butamisole, butamoxane, butanilicaine, butanserin, butantrone,butaperazine, butaprost, butaverine, butedronate, bytenafine,buterizine, butenamate, buthiazide, butibufen, butifrine, butikacin,butilfenin, butinazocine, butinoline, butirosin, butixirate, butixocort,butobendine, butoconazole, butocrolol, butoctatnide, butaftolol,butonate, butopamine, butopiprine, butoprozine, butopyrammonium,butorphanol, butoxamine, butoxylate, butriptyline, butropium,butylscopolamine, butynamine, buzepide, cabastine, cabergoline,cactinomycin, cadralazine, cadrofloxacin, cafaminol, cafedrine,caffeine, calcifediol, calciprotriene, calcitriol, calcobutrol,caldaret, caldiamine, calteridol, clausterone, camazepam, cambendazole,camaglibose, camiverine, camptothecin and its analogues, such as 9-aminocamptothecin, 10-hydroxy camptothecin, 7-ethyl-10-hydroxy camptothecin,9-nitro camptothecin and all other camptothecin analogues with six,seven and eight membered, lactone rings, camonagrel, camostat,camylofin, canbisol, candesartan, candicidin, candocuronium,candoxatril, candoxatrilat, canertinib, canfosfaminde, cangrelor,cannabinol, canrenoate, canrenone, capectitabine, capobenate, capobenicacid, capravirine, capreomycin, capromorelin, caproxamine, capsaicin,captamine, captodiame, captopril, capuride, carabersat, caracemide,carafiban, caramiphen, carbachol, carbadox, carbamazepine, carbentel,carbasone, carbaspirin, carbazeran, carbazochrome, carbazocine,cabenicillin, carbenoxolone, carbeniide, carbetapentane, carbetocin,carbidopa, carbimazole, carbinoxamine, carbiphene, carbofenotion,carboplatin, carboprost, carboquone, carbubarb, carburazepam,carbutamide, carbuterol, carcainium, carebastine, carfentanil,carfimate, cargutocin, cariporide, carisoprodol, carmantadine, carmofur,carmoterol, carmustine, camidazole, carnitine, carocamide, caroverinc,caroxazone, carperidine, carperitide, carperone, carphenazine,carpindolol, carpipramine, carprazidil, carprofen, capronium, carsalam,carsatrin, cartasteine, cartazolate, carteolol, carubicin, cammonam,carvedilol, carvcitroline, carzelesin, carzenide, casanthranol,casokefaminde, caspofungin, cathine, cathinone, cebaracetam, cedefingol,cefaclor, cefadroxil, cefalonium, cefaloram, cefamandole, cefaparole,cefatriazine, cefazaflur, cefazedone, cefazolin, celbuperazone, cefanel,cefcapene, cefclidin, cefdaloxime, cefdinir, cefditoren, cefedrolor,cefempidone, cefepime, cefetamet, cefetecol, cefetriaole, cefivtril,cefixime, cefinatilen, cefmenoxine, cefmepidium, cefmetazole, ceminox,cefodizime, cefonicid, cefoperazone, ceforanide, cefoselis, cefotaxime,cefotetan, cefotiam, cefovecin, cefoxazole, cofoxitin, cefozopran,cefpimizole, cefpiramide, cefpodoxime, cefprozil, cefquinome, cefrotil,cefroxadine, cefsulodin, cefsumide, ceftazidime, cefterarti, ceftezole,ceftibuten, ceftioflur, ceftiolene, ceftioxide, ceftioxime, ceftriaxone,cefuracetamime, cefuroxime, cefuzonam, celeboxib, celgosivir,celiprolol, cemadotin, cephacetrile, cephadrine, cephalexin,cephaloglycin, cephaloridine, cephalothin, cephapirin, cepharanthine,cephradine, cericlamine, cenivastatin, ceronapril, ceruletide, cetaben,cetalkonium, cetamolol, cetefloxacin, cethexonium, cethromycin,cetiedil, cetilistat, cetirizine, cetocycline, cetopheincol,cetotiamine, cetoxime, cetraxate, cetrimonium, cetylpyridinium,cevimeline, chaulmosplfone, chenodiol, chinofon, chlofibrate,chlophendianol, chloracyzine, chloralose, chlorambusil, chloramines-T,chloramphenicol, chlorazanil, chlorbenoxamine, chlorbetamide,chlorcyclizine, chlordantoin, chlordiazepoxide, chlorditnorine,chlorhexidine, chlorindanol, chlorisondamine, chloramadione,chlormetodrin, chrormezanone, chlormidazole, chlornaphazine,chloroazodin, chloroprednisone, chloroprocaine, chloropyramine,chloroquine, chloroserpidine, chlorothen, chlorothiazide,chlorotrianisene, chloroxine, chloroxylenol, chlorphenesin,chlorpheniramine, chlorphenoctium, chlorphenoxamine, chlorphentermine,chlorproethazine, chlorproguanil, chlorpromazine, chlorpropamide,chlorprothixene, chlorpyrifos, chlortetracycline, chlorthalidone,chlorthenoxazine, chlorzoxazone, cholecalciferol, cholesterol, cholinealfoscerate, choline, chromic chloride, chromonar, ciadox, ciaftalan,ciamexon, cianergoline, cianidanol, cianopramine, ciapilome, cicaprost,cicarperone, ciclactate, ciclafrine, ciclazindol, ciclesonide,cicletanine, cicliomenol, ciclonicate, ciclonium, ciclopirox,ciclopramine, cicloprofen, cicloprolol, ciclosidomine, ciclotizolam,ciclotropium, cicloxilic acid, cicloxolone, cicortonide, cidofovir,cidoxepin, cifenline, cifostodine, ciglitazone, ciheptolane, ciladopa,cilansertron, cilastatin, cilazapril, cilengitide, cilexin, cilnidipine,cilobamine, cilobradine, cilofungin, cilomilast, cilostamicle,cilostazol, ciluprevir, cilutazoline, cimaterol, cimemoxin, cimetidine,cimetropium, cimicoxib, cimoxatone, cinacalcet, cinalukast, ciriameticacid, cinamolol, cinanserin, cinaproxen, cinchophen, cinecromen,cinepazet, cinepazide, cinfenine, cinfenoac, cinfiumide, cingestol,cinitapride, cinmetacin, cinnamaverine, cinnamedrine, cinnarizine,cinnofuradione, cinoctramide, cinodine, cinolazepam, cinoquidox,cinoxacin, cinoxate, cinoxolone, cinoxopazide, cinperene, cinprazole,cinpropazide, cinpromide, cintazone, cintriamide, cinuperone,cioteronel, cipamfylline, cipemastat, ciprafamide, cipralisant,ciprazafone, ciprefadol, ciprocinonide, ciprofibrate, ciprofloxacin,ciprokiren, cipropride, ciproquazone, ciprestene, ciramadol, cirazoline,cirolemycin, cisapride, cisatracurium, cinconazole, cismadinone,cisplatin, cistinexine, citalopram, citatepine, citenamide, citenazone,citicoline, citiolone, cizolirtine, cladribine, clamidoxic acid,clamikalant, clamoxyquin, clanfenur, clanobutin, clantifen,clarithromycin, clavulanate, clazolam, clazoliniine, clazuril,clebopride, clefamide, clemastine, clemeprol, clemizole, clenbuterol,clenpirin, clentiazem, cletoquine, clevidipine, clevudine, clibucaine,clidafidine, clidanac, clindium, climazolam, climbazole, climiqualine,clinafloxacin, clindamycin, clinofibrate, clinolamide, clinprost,clioquinol, clioxanide, cliprofen, cliropamine, clobazam, clobenoside,clobenzepam, clobenorex, clobenztropine, clobetasol, clobetasone,clobutinol, clobuzarit, clocanfamide, clocapramine, clociguanil,clocinizine, clocortolone, clocpumarol, clodacaine, clodanolene,clodazon, clodoxopone, clodronate, clofarabine, clofaiimine, clofenamicacid, clofeniclan, clofenetamine, clofenoxyde, clofevine, clofexamine,clofezone, clofibrate, clofibric acid, clofibride, clofilium,clofucarba, clofoctol, cloforex, clofurac, clogestone, cloguanamil,clomacrin, clomegestone, clometacin, clometherone, clomethiazole,clometocillin, clomifenoxide, clominorex, clomiphene, clomipramine,clomocycline, clomoxir, clonazepam, clonazoline, clonidine, clonitazine,clonixeril, clonixin, clopamide, clopenthixol, cloperastine,cloperidone, clopidogrel, clopidol, clopimozide, clopipazan, clopirac,cloponone, cloprenclol, cloprostenol, cloprothiazole, cloquinate,cloquinozine, cloracetadol, cloranolol, clorazepate, clorazepic acid,clorethane, chlorexolone, clorfenvinos, clorgiline, cloricromen,cloridarol, clorindanic acid, clorindiorie, clormecaine, cloroperone,clorophene, cloroqualone, clorotepine, ciorprenaline, clorsulon,clortermine, closantel, closiramine, clostebol, clothiapine,clothixamide, clotiazepam, cloticasone, clotioxone, clotixamide,clotrimazole, clovoxamine, cloxaceptide, cloxacillin, cloxazolam,cloxestradiol, cloximate, cloxotestosterone, cloxypendyl, cloxyquin,clozapine, cobalamide, cocaine, codeine, codoxime, cofistatin,cogazocine, colchicines, colestolone, colfenamate, colforsin,colfosceril, colimecycline, colterol, coluracetam, conessine, congazone,conivaptan, conorphone, cormethasone, corticorelin, cortisone,cortisuzol, cortivazol, cortodoxone, cotinine, cotriptyline, coumaphos,coumazolin, coumennycin, coumetarol, creatinine, creatinolfosfate,cresotamide, cridanimod, crilvastin, crisnatol, crobenetine,croconazole, cromakalim, cromitrile, cromoglicate lisetil, cromolyn,crolom, cronidipine, cropropamide, crotamiton, crotetamide,crotoniazide, crotoxyfos, crufomate, cuprimyxin, cuproxoline,cyacetacide, cyamemazine, cyanocobalamine, cyclacillin, cyclamate,cyclamic acid, cyclandelate, cyclarbamate, cyclazocine, cyclazodone,cyclexanone, cyclindole, cycliramine, cyclizine, cyclobarbital,cyclobendazole, cyclobenzaprine, cyclobutoic acid, cyclobutyrol,cyclocumarol, cyclofenil, cycloguanil, cycloheximide, cyclomenol,cyclomethypaine, cyclopentamine, cyclopenthiazide, cyclopentolate,cyclophenazine, cyclophosphamide, cyclopregnol, cyclopyrronium,cycloserine, eyelothiazide, cyclovalone, cyclotiamine, cycrimine,cyfluthrin, cyhalothrin, cyheptamide, cyheptropine, cynarine,cypenamine, cypermethrin, cypothrin, cyprazepam, cyprenorphine,cyprodenate, cyproheptadine, cyprolidol, cyproquinate, cyproterone,cyproximide, cyromazine, cysteamine, cysteine, cystine, cytarabine,cythiolate, dabelotine, dabigatran, dabuzalgron, dacarbazine,dacemazine, dacinostat, dacisteine, dacopafant, dactinomycin,dacuronium, dagapamil, dagluril, dalbavancin, dalbraminol, dalcotidine,daledalin, dalfopristin, dalteparin, daltroban, dalvastatin,dametralast, damotepine, danazol, daniquidone, danittracen,danolloxacin, danosteine, dafithron, dantrolene, dapiprazole, dapitant,dapiviline, dapoxetine, dapsone, daptomycin, darbufelone, darenzepine,darglitazone, darifenacin, darodipine, daruriavir, darusentan,dasantafil, dateliptium, daunorubicin, daxalipram, dazadrol, dazepinil,dazidamine, dazmegrel, dazolicine, dazoptide, dazoquinast, dazoxiben,deboxament, debrisoquin, decamethonium, decimemide, decitabine,decitropine, declenperone, declopramide, decloxizine, decominol,decoquinate, dectaflur, deditonium, deferasirox, deferiprone,deferoxamine, deflazacort, defosfamine, defoslimod, degarelix,dehydroacetic acid, dehydrocholic acid, dehydroemetine, delanterone,delapril, delavirdine, delguamine, deergotrile, delfantrine,delfaprazine, selmadinone, delmetacin, delmpinol, delorazepam,deloxolone, delprostenate, delucemine, dembrexine, demecarium,demeclocycline, demecolcine, demecycline, demegestone, demelverine,demexiptiline, democonazole, demoxepam, demoxytocin, denatonium,denaverine, denbufylline, denipride, denofungin, denopamine, denotivir,denpidazone, denufosol, denzimol, depelestat, depramine, depreotide,deprodone, deprostil, deptropine, degualinium, deracoxib, deramciclane,deriglidole, derpanicaine, dersalazine, desapidin, desciclovir,descinolone, deserpidine, desipramine, deeslanoside, desloratidine,deslorelin, desmeninol, desmethylmoramide, desmopressin, desocriptine,desogestrel, desmorphine, desonide, desoximetasone,desoxycorticosterone, desvenlafaxine, detajmium, detanosal, deterenol,detirelix, detiviciclovir, detromidine, detorubicin, detrothyronine,devapamil, devazepide, dexamethasone, dexamisole, dexbrompheniramine,dexbudesonide, dexchlorpheniramine, dexclamol, dexecadotril,dexefaroxan, dexetimide, dexetozoline, dexfenfiuramine, dexfosfoserine,dexibuprofen, deximafen, dexindoprofen, dexivacaine, dexketoprofen,dexlofexidine, dexloxiglumide, dexmedetomidine, dexmethylphenidate,dexnafenodonee, dexniguldipine, dexnorgestrel, dexormaplatin,dexoxadrol, dexpanthenol, dexpemedolac, dexpropranolol, dexproxibutene,dexrazoxane, dexsecoverine, dexsotalol, dextilidine, dextiopronin,dextofisopam, dextroamphetamine, dextrofemine, dextromethorphan,dextromoramide, dextrorphan, dextrothyroxine, dexcerapimil, sezaguanine,dezinamide, dezocine, diacerein, diacetamate, diacetolol, diamfenetide,diamocaine, diampromide, diamthiazole, diapamide, diarbarone,diathymosulfone, diatrizoate, diaveridine, diazepam, diaziquone,diazoxide, dibekacin, dibemethine, dibenzepin, dibenzothiophene,dibrompropamidine, bibromsalan, dibrospidium, dibucaine, dibuprol,dibupyrone, dibusadol, dicarbine, dicarfen, dichloralphenazone,dichloramine, dichlorisone, dichlormezanone, dichlorophen,dichlorphenarsine, dichloroxylenol, dichlorphenamide, dichlovos,diciferron, dicirenone, diclazuril, diclofenac, diclofenamide,diclofensine, diclofutrime, diclometide, diclonixin, dicloralurea,dicloxacillin, diclolinium, dicummol, dicyclomine, didanosine,didrovaltrate, dieldrin, dienestrol, dienogest, diethadione,diethylphthalate, diethylcarbamazine, dietylpropion, diethylstilbestrol,dethylthambutene, dietyltoluamide, dietifen, difebarbamate, difemerine,difemetorex, difenatnizole, difencloxazine, difenoximide, difenoxin,difetarsone, difeterol, diflomotecan, diflorasone, difloxacin,difluanine, diflucortolone, diflumidone, diflunisal, difluprednate,diftalone, digitalis, digitoxin, digoxin, dihexyverine, dihydralazine,dihydrocodeine, dihydroergotamine, dihydrostreptomycin,dihydrotachysterol, diisobutylaminobenzoyloxypropyl theophylline,diisopromine, diisopropanolamine, diisopropylamine, dilazep, dilevalol,dilmefone, diloxanide, diltiazem, dimabefylline, dimadectin, dimecamine,dimeelonium, dimecrotic acid, dimefadane, dimefline, ditnelazine,dimenhydrinate, dimenoxadol, dimepheptanol, dimepranol, dimepregnen,dimepropion, dimeprozan, dimesna, dimesone, dimetacrine,dimetamfetamine, dimethadione, diinethazan, dimethisoquin,dimethisterone, dimetholizine, dimethothizine, dimethoxanate,dimethylaminoethyl reserpilinate, dimethylthambutene,dimethyltubocurarinium, dimetipirium, dimetofrine, dimetridazole,diminazene, dimiracetam, dimoxamine, dimoxaprost, dimoxyline, dimpylate,dinaline, dinazafone, diniprofylline, dinitolmide, dinoprost,dinoprostone, dinsed, diohippuric acid, diosmin, diotyrosine, dioxadrol,dioxamate, dioxaphetyl butyrate, dioxation, dioxethedrin, dioxifedrine,dioxybenazone, dioxyline, dipenine, diperodon, diphemanil, diphenadione,diphenan, diphenchloxazine, diphenhydramine, diphenidol, diphenoxylate,diphenylpiperidinomethyldioxolan, diphenylpyraline, diphenoxazide,dipipanone, dipiproverine, dipivefrin, diprafenone, diprenorphine,diprobutine, diprofene, diprogulic acid, diproleandomycin, diprofylline,diproqualone, diproteverine, diprotrizoate, diproxadol, dipyridamole,dipyrithione, dipyrocetyl, dipyrone, diquafosol, dirithomycin,dirlotapide, disermolide, disquonium, disobutamide, sidofenin,sdisogluside, disopyramide, disoxaril, distigmine, disufenton,disulergine, disulfamide, disulfuram, disuprazoole, ditazole, ditekiren,ditercalinium, dithiaanine, ditiocade, ditiocarb, ditiomustane,ditolamide, ditophal, divabuterol, divalproex, divaplon, dixanthogen,dizatrifone, dizcilpine, dobesilate, dobupride, dobutamide, dobutamine,docarpamine, docebenone, docetaxel, doconazole, doconexent, docosanol,docusate, dodeclonium, dodicin, dofamium, dofequidar, dofetilide,dolasetron, doliracetam, domazoline, domiodol, domiphen, domipizone,domitroban, domoprednate, domoxin, domperidone, donepezil, donetidine,donitriptan, dopamantine, dopamine, dopexamine, dopropidil, doqualast,dorampimod, doramectin, doranidazole, dorastine, soreptidei, doretinel,doripenem, dorzolamide. dosergoside, dosmalfate, dotarizine, dotefonium,dothiepin, doxacurium, doxapram, doxaprost, doxazosin, doxefazepam,doxenitoin, doxepine, doxergocalciferol, doxibetasol, doxifluridine,doxofylline, doxorubicin, doxpicoinine, doxycycline, doxylamine,drafiazine, dramedilol, draquinolo, drazidox, dribendazolew, drimidene,drobuline, drocinonide, droclidinium, drofenine, droloxifene,drometrizole, dromostanolone, dronabinol, drinedarone, dropempine,droperidol, droprenilamine, dropropizine, drospirenone, drotaverine,drotebanol, droxacin, droxicamide, droxicam, droxidopa, droxinavir,droxypropine, duazomycin, dulofibrate, duloxetine, dulozafone,dumorelin, dumetacin, duoperone, dupracetam, dutasteride, dyclonine,dyhydrogestrone, dymanthine, dyphylline, ebalzotan, ebastine,eberconazole, ebiratide, ebrotidine, ebselen, ecabapide, ecabet,ecadotril, ecalcidene, ecamsule, ecastolol, ecenofloxacin,echothiophate, ecipramidil, eclanamine, eclazolast, ecomustine,econazole, ecopipam, ecraprost, ectylurea, edaglitazone, edaravone,edatrexate, edelfosine, edetol, edifolone, edogestrone, edonentan,edotecarin, edotreotide, edoxudine, edratide, edronocaine, edrophonium,efaproxiral, efaroxan, efavirenz, efegatran, efepristin, efetozole,efletirizine, eflornithine, efloxate, eflucimibe, elfumast, efonidipine,efrotomycin, egarioprost, eglumetad, egtazic acid, equalen, elacridar,elantrine, elanzepine, elaarofiban, elbanizine, eldacimibe, eletriptan,elfazepam, elgotipine, elinafide, eliprodil, elisartan, ellagic acid,elliptinium, elmustine, elnadipine, elopiprazole, elsamitrucin,eltanolone, eltenac, eltoprazine, elucaine, elyucitabine, elzasonan,elziverine, emakalim, emapunil, embramine, embusartan, embutramide,emedastine, emepronium, emetine, emeglitate, emilium, emiteflur,emiverine, emodepside, emopamil, emorfazone, emtricitabine, emylcamate,enadoline, enalapril, enalaprilat, enalkireri, enazadrem, enbucrilate,encamide, enciprazine, enclomiphene, encyprate, endixaprine, endomide,endralazine, endiysone, enecadin, enefexine, enestebol, enfenamic acid,enfluvirtide, englitazone, eniclobrate, enilconazole, enilospirone,eniluracil, eniporide, enisoprost, enloplatin, enocitabine, enofelast,enolicam, enoxacin, enoxantast, enoxaparin, enoximone, enoxolone,enipiprazole, enpiroline, enprazepine, enprofylline, enpromate,enprostil, enramycin, enrasentan, enrofloxacin, ensacillin, ensulizole,entacapone, entecavir, entsulfon, enviomycin, enviradene, enviroxime,enzacamene, anzastaurin, epalrestat, epanolol, eperezolid, eperisone,epervudine, ephedrine, epicamide, epicillin, epicriptine, epiestriol,epimestrol, epinastine, epinephrine, epinepheryl, epipropidine,epirizole, apiroprim, epirubicin, epitetracycline, epithiazide,epitiostanol, eplerenone, elivanserin, epoprostenol, epostane,eprazinone, eprinomectin, epristeride, eprobemide, eprosartan,eprovafen, eproxindine, eprozinol, epsipranel, epaloprost, eptapirone,eptaplatin, eptastigmine, eptazocin, eptifibatide, equillin, erbulozole,erdosteine, ergocalciferol, ergonovine, ergotamine, eritoran, erizepine,erlotinib, ercamide, ersentilide, ertapenem, ertiprotafib, erythritytetrnitrate, erythromycin, esafloxacin, esaprazole, esatenolol,escitalopram, esculamine, eseiidine, esflurbiprofen, esketamine,escarbazepine, esmolol, esomeprazole, esonarimod, esorubicin,esoxybutynin, espatropate, esproquin, estazolam, estradiol,estramustine, estrazinol, estriol, estrofurate, estrone, estropipatenesupone, eszopclone, etabenzarone, etacepride, etafedrine, etafenone,etalocib, etamestrol, etaminile, etamiphylline, etamocycline,etanidazole, etanterol, etaqualone, etarotene, etasuline, etazepine,etazolate, etebenecid, eterobarb, etersalate, ethacridine, ethacrynicacid, ehtambutol, ethamivan, ethamsylate, ethaverine, ethenzameide,ethiazide, ethinamate, ethinyl estradiol, ethionamide, ethisterone,ethoheptazine, ethomoxane, ethonam, ethopabate, ethopropazine,ethosuximide, ethotoin, ethoxazene, ethoxazorutoside, ethoxzolamide,ethybenztropine, ethyl biscoumacetate, ethyl carfluzepate, ethylcartrizoate, ethyl dibunate, ethyl dirazepate, ethyl loflazepate,ethylestrenol, ethylhydrocupreine, ethylmethylthiambutene,ethylmorphine, ethylnorepinepherine, ethylstilbamine, ethylnerone,ethylnodil, ethypicone, etibendazole, eticlopride, etidocaine,etidronate, etidronic acid, etifelmine, etifenin, etifoxine,etilamfetamine, etilefrine, etilevodopa, etinidine, etipirium,etprendol, etiproston, etiracetam, etiroxate, etisazole, etisomicin,etisulergine, etizolam, etocarlide, etocrylene, etodolac, etodroxizine,etofamide, etofenamate, etofenprox, etofibrate, etofermin, etotiaradine,etofylline, etoglucid, eorolex, etolotifen, etoloxamine, etomidate,etomidoline, etomoxir, etomitazene, etonogestrel, etoperidone,etoposide, etoprindole, etoprine, etoricoxib, etorphine, etosalamide,etoxadrol, etoxeridine, etozolin, etrabamine, etravirine, etretinate,etriciguat, etryptamine, etymemazine, eucaine, eucalyptol, eugenol,euprocin, evandamine, evernimicin, everolimus, evicroinil, exalamide,exametazime, examorelin, exaprolol, exatecan, exemestane, exepanol,exifone, exiprofen, exisulind, ezetimibe, ezlopitant, fadolmidine,fadrozole, falecalcitriol, falintolol, falipamil, falnidamol,famciclovir, famirapinium, famotidine, famotine, fampridine,famprofazone, fampronil, fananserin, fanapanel, fandofloxacin,fandosentan, fanetizole, fantofarone, fantridone, farglitazar,fasidotril, fasiplon, fasoracetam, faudil, fazalinium, fazarabine,febantel, febarbamate, febuprol, febuverine, febuxostat, feclemine,feclobuzene, fedotozine, fedrilate, felbamate, felbinac, felipyrine,felodipine, feloprentan, felypressin, femoxetine, fenabutene,fenacetinol, fenaclon, fenadiazole, fenaftic acid, fenalamide,femalcomine, fenamifuril, fenamole, fenaperene, fenbendazole,fenbenicillin, fenbufen, fenbutreazate, fencamfamin, fencibutirol,fenclexonium, fleclofenac, fenclonine, fenclorac, fenclozic acid,fendiline, fendizoate, fendosal, feneritrol, fenestrel, fenethazine,fenethylline, fenetradil, fenfiumizole, fenfluramine, flenfluthrin,fengabine, fenharmane, fenimide, feniodium, fenipentol, fenirfibrate,fenisorex, fenitrothion, fenleuton, fenmetozole, fenmetraminde, fenobam,fenocinol, fenocitimine, fenofibrate, fenoldopam, fenoprofen, fenoterol,fenoerine, fenoxazoline, fenoxedil, fenozolone, fenpentadiol, fenperate,fenprpalone, fenpipramide, fenpiprane, fenpiverinium, fenprinast,fenproporex, fenprostalene, fenquiaone, fenretinide, fenspiride,fentanyl, fenthion, fentiazac, fenticlor, fenticonazolem, fentonium,fenvalerate, fenyripol, fepentolic acid, fepitrizol, fepradinol,feprazone, fepromide, feprosidnine, ferpifosate, fesoterodine,fetoxylate, fexicaine, fexinidazole, fexofenadine, fezatione,fezolamine, fiacitabine, fialuridine, fibracillin, ficlarestat,fidexaban, fiduxosin, figopitant, filaminast, filenadol, ftlipin,finafloxacin, finasteride, fingolimod, fipamezole, fipexide, fipronil,firocoxib, flavamine, flavodic acid, flavodilol, flavoxate, flazalone,flecainide, flerobuterol, fleroxacin, flesinoxan, flestolol, fletazepam,flezelastine, flibanserin, flindokalner, flocalcitriol, floctafenine,flomoxef, floptopione, florantyrone, flordipine, floredil, florfenicol,florifenine, flosatidil, flosequinan, flosulide, flotrenizine,floverine, floxacillin, floxacrine, floxuridine, flucizine, flualamine,fluanisone, fluazacort, fluazuron, flubanilate, flubendazole,flubepride, fluearbtil, flucetorex, flucindole, flucinprazine,flucloronide, fluconazole, flucrylate, flucytosine, fludalanine,fludarabine, fludazonium, fludeoxyglucose, fludiazepam, fludorex,fludoxopone, fludrocortisone, flufenamic acid, flufenisal, flufosal,flufylline, flugestone, fluindarol, fluindione, flumazenil, flimecinol,flumedroxone, flumequine, flumeri done, flumethasone, flumethiazole,flumetramide, flumexadol, flumezapine, fluminorex, flumizole,flumoxonide, flunamine, flunarizine, flunidazale, flunisolide,flunitrazepam, flunixin, flunoprost, flunoxaprofen, fluocinol one,fluocinonide, fluocortin butyl, flubcortolone, fluorescein, fluoresone,fluorodopa, fluorometholone, fluorosalan, fluorouracil, fluotracen,fluoxetine, fluoxymesterone, fluparoxan, flupentixol, fluperamide,fluperlapine, fluperolone, flupheazine, flupimazine, flupirtine,flupranone, fluprazine, fluprednidene, fluprednisolone, fluprofen,fluprofylline, fluproquazone, fluprostepol, fluquazone, fluradoline,flurandrenolide, flurantel, flurazepam, flurbiprofen, fluretofen,flurithromycin, fluorocitabine, fluorofamide, fluorogestone, flusoxolol,fluspiperone, fluspirilene, flutamide, flutazolam, flutemazepam,flutiazin, fluticasone, flutizenol, flutomidate, flutonidine,flutoprazepam, flutrimazole, flutroline, flutropium, fluvastatin,fluvoxamine, fluzinamide, fluzoperine, fodipir, folic acid, fomepizole,fomidacillin fominoben, fomiversen, fomocaine, fonazine, fondaparinux,fopirtbline, forasartan, forferiimex, formebolone, formestane,forinetorex, forminitrazole, formocortal, formoterol, forodesine,foropafant, fosamprenavir, fosarilate, fosazepam, fosenazide,fosfluconazole, fosfocreatinine, fosfomycin, fosfonet, fosfosal,fosfructose, fosinopril, fosinoprilat, fosmenic acid, fosmidomycin,fosopamine, fosphenyloin, fospirate, fpsquidone, fostedil, fosrtriecin,fosveset, fotemustine, fortrenamine, fozivudine, frabuprofen,fradafiban, frakefamide, framycetin, frentizole, freselestat,fronepidil, fropenem, frovatriptan, froxiprost, ftaxilide, ftivazide,ftormetazine, ftorpropazine, fubrogonium, fudosteine, fuladeotin,fulvestrant, fumagillin, fumoxicillin, fungimycin, fuprazole, furacrinicacid, furafylline, furalazine, furaltadone, furaprofen, furazabol,furazolidone, furazolium, furbicillin, furcloprofen, furegrelate,furethidine, furfenorex, furidarone, furmethoxadone, fumidipine,furobufen, furodazole, furofenac, furomazine, furomine, furosemide,furostilbestrol, fursalan, fursultiamine, furtherene, furtrethonium,fusafungine, fusidate, fusidic acid, fuzlocillin, gabapentin,gabapexate, gaboxadol, gacyclidine, gadobenate, gadobutrol, gadocolecticacid, gadodiamine, gadofosveset, gadomelitol, gadopenamide,gadopentetate, gadoteric acid, gadoteridol, gadoversetamide, gadoxetate,gadoxeticaicid, galamustine, galntamine, galarubicin, galasomite,galdansetron, gallamine triethiodide, gallopamil, galoditabine,galosemide, galtifenin, gamfexine, gamolenic acid, gamaxolone,ganciclovir, ganefromycin, ganglefene, ganstigmine, gantacurium,gantofiban, gapicomine, gapromidine, garenoxacin, gatifloxacin,gavestinel, geclosporin, gedocarnil, gefarnate, gefitinib, gemazocine,gemcabene, gemcadiol, gemcitabine, gemeprost, genfibtrozil,gemifloxacin, gemopatrilat, gentamicin, gepefrine, gepirone, geroquinol,gestaclone, gestadienol, gestodene, gestonorone, gestrinone,gevotroline, gimatecan, gimeracil, giparmen, giracodazole, giractide,girisopam, gitaloxin, gitoformate, glafenine, glaspimod, glatirameracetate, glemanserin, glenvastatin, gliamilide, glibotnuride,glibutimine, glicaramide, glicetanide, gliclazide, glicondamine,glidazamide, glifiumide, glimepiride, glipalatnide, glipizide,gliquidone, glisamuride, glisentide, glisindamine, glisolamide,glisoxepide, gloxazone, gloximonam, glucametacin, glucosamine,gluronolactone, glucuronamide, glunicate, glyburide, glybuthiazole,glubuzole, gycopyrrolate, glycylamide, glyhexamide, glymidine,glyoctamide, glyparamide, glypinamide, glyprothiazole, glysobuzole,goralatide, goserelin, gramicidin, granisetron, grepafloxacin,griseofulvin, guabenxan, guacetisal, guafecainol, guaiactamine,guaiapate, guaietolin, guaifenesin, guaimesal, guaisteine, guaithylline,guanabenz, guanacline, guanadrel, guanazodine, guanclofine, guancydine,guanethidine, guanfacine, guanisoquin, guanoclor, guanoctine,guanoxabenz, guanoxan, guanoxyfen, gusperitims, halazepam, halazone,halcinonide, halethazole, halobetasol, halocortolone, halofantrine,halofenate, halofugihone, halometasone, halonamine, halopemide,halopenium, haloperidol, halopredone, haloprogesterone, haloprogin,haloxazolam, haloxon, haloqionol, hamycin, hedaquinium, heliomycin,hepronicate, heptabarbital, heptaverine, heptolamide, hepzidine, heroin,hetacillin, hetaflur, heteronium, hexachlorophene, hexacyclonate,hexacyprone, hexadiline, hexafluorenium, hexamethonium,hexaminolevulinate, hexapradol, hexaprofen, hexapropymate, hexasonium,hexazole, hexedine, hexestrol, hexetidine, hexobarbital, hexobendine,hexocyclium, hexoprenaline, hexopyrronium, heylcaine, histamine,histapyrrodine, histidine, honiarylamine, homatropine, homidium,homochlorcyclizine, homofenazine, homopipramol, homosalate,homprenorphine, hopantenic acid, hoquizil, hycanthone, hydracarbazine,hydralazine, hydragaphen, hydrobentizide, hydrochlorothiazide,hydrocodone, hydrocortisone, hydroflumethiazide, hydromadinone,hydromorphinol, hydromorphone, hydroquinone, hydroxyindasate,hydroxyindasol, hydro xocobalamin, hydroxyamphetamine,hydroxychloroquin, hydroxydione, hydroxypethidine, hydroxyphenamate,hydroxyprocaine, hydroxyprogesterone, hydroxypyridine tartrate,hydroxystenozole, hydroxystilbathidine, hydroxytetracaine, hydroxyzine,hymecromone, hyoscyamine, ibafloxacin, ibandronate, ibazocine,ibopamine, ibrolipim, ibrotamide, ibudalast, ibufenac, ibuprofen,ibuproxam, ibutamoren, ibuterol, ibutilide, ibuverine, icaridin,icatibant, iclaprim, icazepam, icodulinium, icofungipen, ifometasone,icopezil, icosapent, icospiramide, icotidine, icrocaptide, idarubicin,idaverine, idazoxan, idebenone, idenast, idoxifene, idoxuridine,idralfidine, idramantone, idraparinux idrapril, idremcinal,idrociliamide, idronoxil, idropranolol, iferanserin, ifetroban,ifosfamide, ifoxetine, iganidipine, igmesine, iguratimod, ilaprazole,ilatreotide, ilepcimide, iliparcil, ilmofosine, iloomastat, ilonidap,iloperidone, imafen, imanixil, imatinib, imazodan, imcarbofos,imiclopazine, imidafenacin, imidapril, imidaprilat, imidocarb,imidoline, imidurea, intiglitazar, ittiloxan, iminophenimide, imipenem,imipramine, ithipraminoxide, imiquimod, imirestat, imitrodast,imolamine, imoxiterol, impacarzine, implitapide, impromidine,improsulfan, imuracetam, inamirone, inaperisone, incadronic acid,indacaterol, indacrinone, indalpine, indanazoline, indanidine,indanorex, indapamide, indatraline, indecamide, indeloxazine, indenolol,indibulin, indigotindisulfonate, indinavir, indiplon, indisetron,indobufen, indocate, indocyanine green, indolapril, indolidan,indomethacin, indopanolol, indopine, indoprofen, indoramin, indorenate,indoxole, indriline, inecalcitol, ingliforib, inicarone, inocteroneacetate, inogatran, inosine, inositol, improquoone, intoplicine,intrazole, intriptyline, inulin, iobenguane, iobenzamic acid,iobitridol, iobutoic acid, icanlidic acid, iocarmic acid, iocetamieacid, iodatnine, iodipamide, iodixanol, iodoantipyrine, iodocholesterol,iodohippurate, iodoquinol, iodothiouracil, idoxamic acid, iofetamine,ioflupane, iofratol, ioglicic acid, ioglucol, ioglunide, ioglycamicacid, iogulaamide, iohexyl, iolidonic acid, iolixanic acid, iolopride,iomazenil, ipmeglamicacid, iomeprol, iomethin, iometopane, ipmorinicacid, iopamidol, iopanoic acid, iopentol, iophendyfate, iophenoxic acid,iopromide, iopronic acid, iopydol, iopydone, iosarcol, isofenamic acid,ioseric acid, iosimenol, iosimide, iosulamide, iosumetic acid, iotasul,ioseric acid, iothalamate, iothalamic acid, iotranic acid, iotriside,iotrizoic acid, iotrolan, iotroxic acid, iotyrosine, iovesol, ioxabrolicacid, ioxaglic acid, ioxilan, ioxitalamic acid, ioxotrizoic acid,iozomic acid, ipamorel in, ipazilide, ipenoxazone, ipexidine,ipidacrine, ipodate, iprgratine, ipramidil, ipratropium, ipravacaine,iprazochrome, ipriflavone, iprindole, ipocinidine, iproclozide,iprocrodol, iprofenin, iproheptine, iproniazide, ipronidazole,iproplatin, iprotiazem, iproxamine, iprozilamine, ipsalazide,ipsapirone, iquindamine, iralukast, irampanel, irbesartan, irindalone,irinotecan, irloxacin, irofulven, irolapride, iroxanadine, irsogladine,irtemazole, isalidole, isalsteine, isamfazone, isamoltan, isamoxole,isatoribine, isaxonine, isbogrel, isbufylline, ispainicin,isoarriilinile, isobromindione, isobucaine, isobutamben, isocarboxazid,isoconazole, isocromil, isoetharine, isofiupredone, isofluorophate,isomazole, isomerol, isometamidium, isomethadone, isometheptene,isomolpan, isoamylamine, isoniazid, isonixin, isoprazole, isoprednidene,isoprofen, isopropamide, isopropicillin, isoproterenol, isostbide,isospaglumic acid, isosulfan blue, isosulpride, isothipendyl,isotiquimide, isotretinoin, isoxaprolol, isoxepac, isoxicam,isoxsuprine, isradipine, israpafant, istrdefylline, itameline,itanoxone, itasetron, itazigrel, itopride, itraconazole, itriglumide,itrocamide, itrocinonide, iturelix, ivbradine, ivarimod, ivermectin,ivoqualine, ixabepilone, izonsteride, josamycin, kainic acid,kalafungin, kanamycin, kebuzone, keracyanin, ketamine, ketanserin,ketazocine, ketazolam, kethoxai, ketipramine, ketobemidone, ketocaine,ketocainol, ketoconazole, ketoprofen, ketorfanol, ketorolac, ketotifen,ketotrexate, khellin, khelloside, kitasamycin, labetalol, labradimil,lachesine, lacidipine, lacosamide, lactalfate, lactilol, lactulose,ladirubicin, ladostigil, lafluriimus, lafutiine, laidlomycin propionate,lamifiban, lamivudine, lamotrigine, lamitidine, lanatoside, landiolol,lanepitant, lanicemine, laniquidar, lanoconazole, lanperisone,lanproston, lanreotide, lansoprazole, lapatinib, lapisteride,laprafylline, lapyrium, laquinimod, lasalocid, lasinavir, lasofoxifene,latanoprost, laudexium, laurcetium, laurocapram, lauroguadine,laurolinium, lauryl isoquinolinium, lavoltidine, lazabemide, lecimibide,ledazerol, ledoxantrone, lefetamine, leflunomide, lefradafiban,leiopyrrole, lemidosul, lemidipine, leminoprazole, lemoxinol,lemuteporfin, lanalidomine, lenanipicillin, lenapenem, leniquisin,leuperone, leptacline, lercanidipine, lergotrile, lerisetron,lesoptiron, lestaurtinib, leteprinim, leteprinim, letimide, letosteine,letrazuril, letrozole, leucinocaine, leucocianidol, leucovorin,leurubicin, levalbuterol, levallorphan, levamfetamine, levamisole,levcromakalim, levcycloserine, levdobutamine, levemoamil, levetiracetam,levisoprenaline, levlofexidine, levmetamfetamine, levobetaxolol,levobunolol, levobupiacaine, levocabastine, levocamitine, levodopa,levodropropizine, levofacetoperane, levofenfluramine, levofloxacin,levofluraltadone, levoleucovorin, levomenol, levomepromazine,levomethadone, levomethadyl acetate, levomethorphan, levometiomeprazine,levomoprolol, levotnoramide, levonantradol, levonordefrin,levonorgestrel, levophenacylmorphan, levopropoxyphene,levopropylcilline, levopropuylhexedrine, levoprotiline, levorin,levormeloxifene, levorphanol, levosalbutamol, levosemotiadil,levosimendan, levosulpiride, levothyroxine, levotofisopam, levoeadrol,lexipafant, lexithromycin, lexofenac, liarozole, libecillide,libenzapril, licarbazepine, licofelone, licostinel, lidadronic acid,lidamine, lidanserin, lidocaine, lidoferin, lidorestat, lifariaine,lifibrate, lifibrol, lilopristone, limaprost, limazocic acid,linarotene, lincomycin, lindane, linetastine, linezolid, linogliride,linopirdine, linotroban, lisinidomine, lintitript, lintopride,liothyronine, lipoic acid, liraglutide, liranaftate, lirequinil,lirexapride, lirimilast, liroldine, lisadimate, lisinopril, lisofylline,lisuride, litomeglovir, litoxetine, litracen, lividomycin, lixazinone,lixivaptan, lobapolatin, lobeline, lobendazole, lobenzarit, lobucavir,lobuprofen, locicortolone, lodaxaprine, lodazecar, lodelaben,lodenosine, lodinixil, lodiperone, lodoxamide, lofemizole, lofendazam,lofentanil, lofepramine, lofexidine, loflucarban, lombazole,lomefloxacin, lomeguarib, lomerizine, lometraline, lometrexol,lomevactone, lomifylline, lomofungin, lomustine, lonafarnib, lonapalene,lonaprofen, lonazolac, lonidamine, loperamide, lopinavir, lopirazepam,lopobutan, loprazolam, loracarbef, lorajmine, lorapride, lorazepam,lorbamate, lorcamide, lorcinadol, loreclezole, lorglumide, lormetazepam,lornoxiaam, lopiprazole, lortalamine, lorzafone, losartan, losigamone,losindole, lostniprofen, losoxantrone, losulazine, loteprednol,lotrafiban, lotrifen, lotucaine, lovastatin, loviride, loxanast,loxapine, loxiglumide, loxoprofen, loxoribine, lozilurea, lubazodone,lubeluzole, lubiprostone, lucanthone, lucartamide, lucimycin, lufenuron,lufironil, lufuradom, luliconazole, lumiracoxib, lupitidine, luprostiol,lurasidone, lurosetron, lurototecan, lusaperidone, luxabendazole,lydimycin, lymecycline, lynestrenol, lypressin, mabuprofen, mabuterol,maduramicin, mafenide, mafoprazine, mafosfamide, malathion,maleylsulfathiazole, malotilate, mangafodipir, manidipine, manifaxine,mannomustine, manozodil, mantabegron, mapinastine, maprotiline,maraviroc, marbofloxacin, maribavir, maridomycin, marimastat,mariptiline, maropitant, maroxepin, masoprocol, maxacalcitol,maytansine, mazapertine, mazaticol, mazindol, mazipredone, mazokalim,mebanazine, mebendazole, menbenoside, mebeverine, mebezonium,mebhydrolin, mebiquine, mebolazine, mebrofenin, mebutamate, mebutizide,mecamylamine, mecarbinate, mecetronium, meciadanil, mecinarone,meclinertant, meclizine, meclocycline, meclofenamaic acid,meclofenoxate, meclonazepam, mecloqualone, meclorisorte dibtityrate,mectoxamine, mecobalamin, medazepam, medazomide, medetomidine,mededibazine, medifoxamine, medorinone, medorubicin, medrogestrone,medronic acid, medroxalol, medroxyprogesterone acetate, medrylamine,medrysone, mefeclorazine, mefenamic acid, mefenidil, mefertidramium,mefenorex, mefeserpine, mefexamide, mefloquine, mefruside, megalomyciin,megestrol, megace, meglitinide, meglucycline, meglumine, meglutol,meladrizine, melagatran, melarsomine, melarsonyl, melarsoprol,meldonium, melengestrol acetate, meletimide, melevodopa, melinamide,melitracen, melizame, meloxicam, melperone, melphalan, melquinast,meluadrine, mamantine, memotine, menabitan, menadiol, menadione,menadoxime, menatetrenone, menbutone, menfegol, menglytate,menitrazepam, menoctone, menogaril, menobentine, mepazine, mepenzolate,meperidine, mephenesin, mephenoxalone, mephentermine, mephenytoin,mephobarbital, mebaral, mepindolol, mepiperphenidol, mepiprazole,mepiroxol, mepitiostane, mepivacaine, mepixanox, mepramidil,meprednisone, meprobamate, meprochol, meproscillarin, meprotixol,meprylcaine, meptazinol, mequidox, mequinol, mequitamium, mequitazine,meradimqate, menthyl anthranilate, merafloxacin, meralein, meralluride,merbaphen, merbromin, mercaptomerin, mercaptopurine, mercuderamide,mercufenol, mercumatilin, mergocriptine, meribendan, merimepodib,meropenem, mersalyl, mertialide, mesabolone, mesalamine, meseclazone,mesocarb, mesoridazine, mesipiperone, mespirenone, mestanolone,mesterolone, mestranol, mesudipine, mesulergine, mesulfamide, mesulfen,mesuprine, metabromsalan, metbutethamine, metabutoxycaine, metacetamol,metaclazepam, metacresol, metaglycodol, metahexamide, metalkonium,metalol, metamelfalan, metamfazone, metamfenpramone, metampicillin,metanixin, metapramine, metaproterenol, metaraminol, metaxalone,metazamide, metazide, matazocine, metbufen, meteneprost, metergoline,metergotamine, metescufylline, metesculetol, metesind, metethoheptazine,metformin, methacholine, methacycline, methadone, methadyl acetate,methallenestril, methallibure, methalthiazide, methamphetamine,methandriol, methandrostenolone, methaniazide, methantheline,methaphenilene, methapyrilene, methaqualone, metharbital,methastyridone, methazolamide, methdilazine, methenamine, methenolone,metheptazine, methestrol, methetoin, methikcillin, methimazole,methiodal, methiomeprazine, methionine, methisazone, methitural,methixene, methocarbamol, methocidin, methohexital, methopholone,methoprene, methoserpidine, methotrexate, methotrimeprazine,methoxamine, methoxsalen, methoxyphethine, methoxyphenamine,methoxypromazine, methscopolamine, methsuximide, methyclothiazide,methyl aminolevulinate, methyl palmoxirate, methyl salicylate,methylatropine, methylbenactyzium, methylbenzethonium, methylcromone,methyldesorphine, methyldihydrotnorphine, methyldopa, methylene blie,methylephedrine, methylergometrine, methylergonovine, methyllparaben,methylphenidate, methylprednisolone, methyltestosterone,methylthiouracil, methynodiol, methyprylon, methysergide, metiamide,metiapine, metiazinic acid, metibride, meticrane, metildigoxin,metindizate, metioprim, metioxate, metipirox, metiprenaline, metitepine,metizoline, metkephamid, metochalcone, metocinium, metoclopramide,metocurine, metofenazate, metogest, metolazone, metomidate,metopimazine, metopon, metoprine, metoprolol, metoquizine, metoserpate,metostilenol, metoxepin, metrafazoline, metralindole, metrazifone,metrenperone, metribolone, metrifonate, metrifudil, metrizamide,metrizoate, metronidiazole, meturedepa, metyrapone, metyrosine,mevastatin, mexafylline, mexazolam, mexenone, mexiletine, mexiprosil,mexoprofen, mexrenoate, mezacopride, mezepine, mezilamine, mezlocillin,miaanserin, mibefradil, mibolerone, miboplatin, micafungin, miconazole,micronomicin, midaflur, midafotel, midaglizole, midamaline,midaxifylline, midazogrel, midazolam, midecamycin, midestein, midodrine,midostaurin, mifentidine, mifepristone, mifobate, miglitol, miglustat,mikamycin, milacamide, milacemide, milameline, milataxel, milenperone,milfasartan, milipertine, miloxacin, milrinone, miltefosine, milverine,mimbane, minalrestat, minamestane, minaprine, minaxolone, mindodilol,mindoperone, minepentate, minocromil, minocycline, minodronic acid,minopafant, minoxidil, mioflaazine, mipitroban, mipragoside,miproxifene, mirfentanil, mirincamycin, mitipirium, miriplatin,mirisetron, miristalkonium, miroprofen, mirosamicin, mirostipen,mirtazapine, misortidazole, misoprostol, mitemcinal, mitiglinide,mitindomine, mitobronitol, mitocarcin, mitoclomine, mitocromin,mitoflaxone, mitogillin, mitoguazone, mitolactol, mitomalcin, mitomycin,mitonafide, mitopodozide, mitoquidone, mitosper, mitolane, mitotenamine,mitoxantrone, mitozolomide, mitradipide, mivacurium, mivobulin,mivotilate, mixidine, mizolastine, mizoribine, mobecarb, mobenzoxamine,mocimycin, mociprazine, moclonemide, moctamide, modafinil, modaline,modecamide, modipafant, moexipril, moexiprilat, mofarotene, mofebtazone,mofegiline, mofezolac, mofloverine, mofoxine, mofuisteine, molfamate,molinazone, molindone, molracetain, molsidoinine, mometasone,monalazone, monatepil, monesin, monobenzone, monoctanoin, momimetacrine,monophosphothiamine, monoxerutin, montelukast, monterelin, moperone,mopidamol, mopidralazine, moprolol, moquizone, morantel, morazone,morclofone, morforex, moricizine, morinamide, momiflumate, morocromen,moroxydine, morpheridine, morphine, morsuximide, mosapramine, mosapride,motapizone, motexafin, motrazepam, motrtinide, moveltipril, moxadolen,moxalactam, moxaprindine, moxastine, moxaverine, moxazocine, moxestrol,moxicoumone, moxidectin, moxifloxacin, moxilubant, moxipraquine,moxirapine, moxisylate, moxnidazole, moxonidine, mozavaptan, mozenavir,mubritnib, mupirocin, murabutide muraglitazar, mureletecan, murocamide,muzolimine, mycophenolic acid, myfadol, myrophine, myrtecaine,nabazenil, nabilone, nabitan, naboctate, nabutnetone, nacartocin,nadide, nadiofloxacin, nadolol, nadoxolol, nafagrel, nafamostat,nafarelin, nafazatrom, nafcaproic acid, nafcillin, nafenodone,nafenopin, nafetolol, nafimidone, nafiverine, naflocort, nafotnine,nafoxadol, nafoxidine, nafronyl, naftalofos, naftazone, naftifine,naftopidil, naftoxate, naftypamide, naglivan, nalbuphine, nalfurafine,nalidixic acid, nalmefene, nalmexone, nalorphine, naloxone, naltrexone,naminidil, naminterol, namirotene, namoxyrate, nanafrocin, nandrolone,nanterinone, nantradol, napactadine, napamezole, naphazaoline,naphthonone, napirimus, napitane, naproxime, naproxen, naproxol,napsagatran, naranol, narasin, naratriptan, nardetoterol, naroparcil,natamycin, nateglinide, navuridine, naxagolide, naxaprosteine,naxifylline, nealbarbital, nebantan, nebidrazine, nebivolol,neboglamine, nebracetam, nebramycin, necopidem, nedaplatin, nedocromil,nefazodone, nefiracetam, neflumozide, nefopam, nelarabine, neldazosin,nelezaprine, nelfinavir, neltenexine, nelzarabine, nemadectin,nemazoline, nemifitide, nemonaptide, nemorubicin, neocinchophen,neomycin, neostigmine, nepadutant, nepafenac, nepaprazole, nepicastat,nepinalone, nequinate, neramexane, neraminol, nerbacadol, neridronicacid, nerisopam, nesapidil, nesiritide, nesosteine, nestifylline,neticonazole, netilmicin, netivudine, netobimin, netoglitazone,netupitant, neutramycin, neviparine, nexeridine, nexopamil, niacin,niacinamide, nialamide, niaprazine, nibroxane, nicafenine, nicainoprol,nicametane, nicanartine, nicaraven, nicarbazin, nicardipine,nicergoline, niceritol, niceverine, niclofolan, niclosamide, nicoboxil,nicoclonate, nicocodine, nicocortonide, nicocidodine, nicoduozide,nicofibrate, nicofuranose, nifurate, nicogrelate, nicomol, nicomorphine,nicopholine, nicoracetam, nicorandil, nicothiazone, nicotredole,nicoxamat, nictiazem, nictindole, nidroxyzone, nifedipine, nifekalant,nifenalol, nifenazone, niflumic acid, nifungin, nifiradene,nifuraldezone, nifuralide, nifuratel, nifuratrone, nifurdazil,nifurethazone, nifurfoline, nifurimide, nifurizone, nifurmazole,nifurmerone, nifuroquine, nifuroxazide, nifurokime, nifurpipone,nifurpirinol, nifirprazine, nifurquinazol, nifursemizone, nifursol,nifurthiazole, nifurtimox, nifurtoinol, nifurvidine, nifurzide,nigludipine, nihydrazone, nikethamide, nileprost, nilprazole,niludipine, nilutamide, nilvadipine, nimazone, nimesulide, nimetazepam,nimidane, nimodipine, nimorazole, nimustane, neometacin, niperotidine,nipradilol, niprofazone, nitavoline, nirdazole, nisbuterol, nisobamate,nisoldipine, nisoxetine, nisterime, nitarsone, nitazoxanide, nitecapone,nithiamide, nitisinone, nitracrine, nitrafudan, nitralamine,nitramisole, nitraquazone, nitrazepam, nitrefazole, nitrendipine,nitrocefin, nitrodofene, nitrocycline, nitroclan, nitrofurantoin,nitrofurazone, nitromersol, nitromide, nitromifene, nitroscanate,nitrovin, nitroxinil, nitroxoline, nivazol, nivimedone, nizatidine,nizofenone, noberastine, nocloprost, nocodazole, nofecamide,nogalamycin, nolatrexed, nolinium, nolomirole, nolpitantium,noniegestrol, nomelidine, nomifensine, nonabin, nonaperone,nonapyrimine, nonathymulin, nonivamide, noracymethadol, norbolethone,norbudroine, norcholestenol, norclostebol, norcodeine, nordazepam,nordefrin, nordinone, norelgestromin, norepinepherine, norethandrolone,noethindrone, norethynodrel, noreximide, norfenefrine, norfloxacin,norgesterone, norgestimate, norgestomet, norgestrel, norgestrieneone,norietimol, norlevorphenol, normethadone, normorphine, norpipanone,nortetrazepam, nortopixantrone, nortriptyline, norvinisterone,nosantine, noscapine, nosiheptide, novobiocin, noxiptiline, noxytiolin,nuclomedone, nuclotixene, nufenoxole, nupafant, nuvenzepine, nylestriol,nylidrin, nystatin, obidoxime, ocaperidone, ocfentanil, ociltide,ocinaplon, octacaine, octafonium, octamoxin, octapinol, octatine,octaverine, octazamide, octenidine, octicizer, octimibate, octinoxate,octisalate, octocrylene, octodrine, octopamine, octotiamine, octreotide,octriptyline, octriazole, odalprofen, odapipam, odiparcil, ofloxacin,ofomine, oftasceine, oglufanide, olaflur, olamufloxacin, olanexidine,olanzapine, olaquindox, olcegepant, pleandomycin, oletimol, olmesartan,olopatadine, olpadronic acid, olpimedone, olprinone, olradipine,olsalazine, oltipraz, olvanil, omaciclovir, omapartrilat, omeprazole,omidoline, omigapil, omiloxetine, omoconazole, omonasteine, onapristone,ondansetron, ontazolast, ontianil, opanixil, opaviraline, opiniazide,opipramol, opratonium, orazamide, orazipone, orbofiban, orbutopril,orconazole, orientiparcin, oritavancin, orlistat, ormaplatin,ormeloxifene, ormetoprin, ornidazole, ornipreessin, ornithine,ornoprostil, orotic acid, orotirelin, orpanoxin, orphenadrine,ortataxel, orteteamine, osanetant, osaterone, oseltamivir, osemozotan,osmadizone, ospemifene, ostreogrycin, osutidine, otamixaban, otenzepad,oteracil, otilonium, otimerate, ouabain, oxabolon, oxabrexine,oxaceprol, oxacillin, oxadimedine, oxaflozane, oxaflumazine, oxagrelate,oxalinast, oxaliplatin, oxamarin, oxametacin, oxamisole, oxaminiquinemoxanamide, oxandrolone, oxantel, oxapadol, oxapium, oxaprazine,oxaprotiline, oxaprozin, oxcarbazole, oxatomide, oxazafone, oxazepam,oxazidone, oxazolam, oxazorone, oxcarbazepine, oxdralazine,oxeclosporin, oxedrine, oxeglitazar, oxeladin, oxendolone, oxepinac,oxethazine, oxetorone, oxfendazold, oxfenicine, oxibendazole,oxibetaine, oxiconizole, oxidapamine, oxidronic acid, oxfentorex,oxifungin, oxigluttione, oxilofrine, oxilorphan, oximonam, oxindanac,oxiniacic acid, oxperomide, oxiracetam, oxiramide, oxisopred, oxisuran,oxitefonium, oxitriptan, oxitriptyline, oxtriponium, oxmetidine,oxodipine, oxogestone, oxolamine, oxolinic acid, oxomermazine,oxonazine, oxophenarsine, oxoprostol, oxpheneridine, oxprenoate,oxprenolol, oxtriphylline, oxbenzone, oxybutynin, oxychlorosene,oxycinchophen, oxyclipine, oxyclozanide, oxycodone, oxydipentonium,oxyfedrine, oxymesterone, oxymetazoline, oxymethaoone, oxymorphone,oxypendyl, oxyprtine, oxyphenbutazone, oxyphencyclimine, oxypheni satin,oxyphenonium, oxypurinol, oxypurronium, oxyquinoline, oxyridazine,oxysonium, oxytetracycline, oxytocin, ozagrel, ozagamicin, ozolindone,paclitaxel, pacrindolol, pactimibe, padimate A, padimate Q, pafenolol,pagoclone, paldimycin, palinavir, paliperidone, palmidrol, palmoxirate,palonidipine, palonosertron, palosuran, pamabron, pamaqueside, pamaquin,pamicogrel, pamidronic acid, panadiplon, panamesine, pancopride,pancuronium, panipenem, panomifene, pantenicate, pantethine, panthenol,pantoprazole, panuramine, papverine, papveroline, parachlorphenol,parafiutizide, paramethadione, paramethasone acetate,paranitrosulfathiazole, paranyline, parapenzolate, parapropamol,pararosaniline, paraxazone, parbendazole, parcetasal, parconazole,parecoxib, pareptide, parethoxycaine, pargeverine, pargolol, pargyline,paricalcitol, paridocaine, parodilol, paromomycin, paroxetine,paroxypropione, parsalmide, particin, parvaquone, pasiniazid,pasireotide, patamostat, patupilone, paulomycin, paxamate, pazelliptine,pazinaclone, pazoxide, pazufloxacin, pecilocin, pecocycline, pefloxocin,pelanserin, peldesine, peliomycin, pelitinib, pelitrexol, pelretin,pelrinone, pelubiprofen, pemedolac, pemerid, pemetrexed, pemirolast,pemoline, penamecillin, penbutolol, penciclovir, pendecamine, pendetide,penfluridol, penflutizide, pengitoxin, penicillamine, penicillin G,penicillin V, penimepicycline, penimocycline, penirolol, penmesterol,penoctonium, penprostene, pentabamate, pentacynium, pentfluranol,pentagastrin, pentagestrone, pentalamide, pentamethonium, pentamidine,pentamorphone, pentamoxane, pentamustine, pentapiperide, pentapiperium,pentaquine, pentazocine, pentetic acid, pentreotide, penthienate,penthrichloral, pentiapine, pentifylline, pentigetide, pentisomicin,pentisomeide, pentizidone, pentobarbital, pentolinium, pentolonium,pentomone, pentopril, pentorex, pentosalen, pentostatin, pentoxifylline,pentoxyverine, pentrinitrol, pentylenetetrazol, peplomycin, pepstatin,peraclopone, peradoxime, perafensine, peralopride, peramivir,peraquisin, perastine, peratizole, perazine, perbufylline, perfomedil,perfosfamide, pegolide, perhexyline, periciazine, perifosine,perimetazine, perindopril, perindoprilat, perisoxal, perlapine,permethrin, perospirone, perphenazine, persilic acid, perzinfotel,petrichloral, pexantel, phanquone, phenacaine, phenacemide, phenacetin,phenactropinium, phenadoxone, phenaglycodol, phenamazoline,phenampromide, phenaphthazine, phenarsone, phenazocine, phenazopyridine,phenbutazone, phencarbamide, phencyclidine, phendimetrazine, phenelzine,pheneridine, phenethicillin, pheneturide, phenylglutarimide,phenicarbazide, phenindamine, phenindione, pheniprazine, pheniramine,phenisonone, phenmetrazine, phenobarbital, phenobutiodil, phenomorphan,phenothiazine, phenothrin, phenoxybenzamine, phenoxypropazine,phenprobamate, phenprocoumon, phenpromethamine, phensuximide,phentermine, phentolamine, phenyl atninosalicylic acid, phenylalanine,phenylbutazone, phenylephrine, phenylpropanolamine, phenylthiolone,phenyltoloxamine, phenyracillin, phenyramidol, phenyloin, pnetharbital,pholcodine, pholedrine, phoxim, phthalofyne, phthylsulfacetamide,phthalylsulfamethiazole, phthalylsulfathiazole, physostigmine. Phyticacid, phytonadione, pibaxizine, pibecarb, piberaline, piboserod,pibrozelesin, pibutidien, picafibrate, picartamide, picenadol,picilorex, piclamilast, piclonidine, piclopastine, picloxydine,picobenzide, picodralazine, picolamine, piconol, picoperine, picoplatin,picoprazole, picotamide, picotrin, picumast, picumeterol, pidobenzone,pidolacetamol, pidolicaicd, pidotimod, pifamine, pifinate, pifexole,piflutixol, piketoprofen, pildralazine, pilocarpine, pilsicamide,pimagedine, pimeclone, pimecrolimus, pimethylline, pimelautide,pimetacin, pimethixene, pimetine, imetremide, pimilprost, piminodine,pimobendan, pimonidazole, pimozide, pinacidil, pinadoline, pinafide,pinaverium, pinazepam, pincamide, pindolol, pinokalant, pinolcaine,pinoxepine, pioglitazone, pipacycline, pipamazine, pipamperone,pipazethate, pipebuzone, pipecuronium, pipemidicacid, pipendoxifene,pipenzolate, pipequaline, piperacetazine, piperacillin, piperamide,piperidolate, piperilate, piperocaine, piperonyl butoxide, piperoxan,piperphenidol, piperylone, pipobroman, pipoctanone, pipofezine,piposulfan, pipotiazine, pipoxizine, pipoxolan, pipradimadol, pipradrol,pipramadol, pipratecol, piprinhydrinate, pipocurarium, piprofurol,piprozolin, piquindone, piquizil, piracetam, pirandamine, pirarubicin,piraxelate, pirzmonam, pirazolac, pirbenicillin, pirbuterol, pirdonium,pirenoxine, pirenperone, pirezepine, pirepolol, piretanide, pirfenidone,pirbendil, piridicillin, piridocaine, piridoxilate, piridronic acid,pirifibrate, pirimiphos-ethyl, pirindazole, pirinixic acid, pirinixil,piriprost, piriqualone, pirisudanol, piritramide, piritrexin,pirlimycin, pirlindole, pirmagrel, pirmenol, pirnabine, piroctone,pirodavir, priodomast, pirogliride, piroheptine, pirolate, pirolazamide,piromidic acid, piroxantrone, piroxicam, piroxidillin, piroximone,pirozadil, pirprofen, pirquinozol, pirralkonium, pirsidomine,pirtenidine, pitenodil, pitofenone, pituxate, pivagabine, pivampicillin,pivenfiine, pivopril, pivoxazepam, pixantrone, pizotyline, plafbride,plaunotol, plauracin, pleconaril, pleuromulin, plevitrexed, plicamuycin,plomestane, pobilukast, podilfen, podofilox, poldine, polymixin,polythiazide, pomisartan, ponalrestat, ponazufil, ponfibrate,porfiromycin, posaconazole, posatirelin, posizolid, poskine, practolol,pradolfoxacin, prajmalium, pralatrexate, pralidoxime, pralmorelin,pralnacasan, pramipexole, pramiracetam, pramoxine, prampine,pranazepide, pranidipine, prankulast, pranolium, pranoprofen, pranosal,prasterone, prasugrel, pratosartan, pravadoline, pravastatin, praxadine,prazarelix, prazepam, prazepine, praziquantel, prazitbrie, prazocillin,prazosin, preclamol, prednazate, prednazoline, prednicarbate,prednimustine, prednisolamate, prednisolone, prednisone, prednival,prednylidene, pregabalin, pregnadiol, pregnenolone, premafloxacin,premazepam, prenalterol, prenisteine, prenoverine, prenoxdiazine,prenylamine, pretamazium, pretiadoil, prezatide, pribecaine, pridefine,prideperone, pridinol, prifelone, prifinium, prifirroline, pilocalne,primaperone, primaquine, primidolol, primidone, primycin, prinomastat,prinomide, prinoxodan, pristinol, pristinamycin, prizidilol, proadifen,probarbital, probenecid, probicromil, probucol, procainamide, procaine,procarbazine, procaterol, prochlorperazine, procinolol, procinonide,proclonol, procromil, procyclidine, procymate, prodeconium, prodilidine,prodipine, prodolic acid, profadol, profexalone, proflavine,proflazepam, progabide, progesterone, proglumetacin, proglumide,proheptazine, praligestone, praline, prolintane, prolonium, promazine,promegestone, promestriene, promethazine, promo late, promoxo lane,prontalol, propacetamol, propafenone, propagermanium, propamidine,propanidid, propanocaine, propantheline, proparacaine, propatyl nitrate,propazolamide, propenidazole, proprntofylline, propenzolate,properidine, propetamide, propetamfos, propetandrol, propicillin,propikacin, propinetidine, propiomazine, propiocaine, propiram,propisergide, propiverine, propizepine, propofol, propoxate, propoxur,propoxycaine, propoxyphene, propranolol, propyl docetrizoate, propylgallate, propylhexedrine, propyliodone, propylthiouracil, propyperone,propyphenazone, propyromazine, proquazone, proquinolate, prorenoate,proroxan, prsciliardin, prospidium, prostalene, prosulpride,prosultiamine, proterguride, protheobromine, prothipendyl, prothixene,protiofate, protionamide, protirelin, protizinic acid, protokylol,protoporphyrin, protriptyline, proxzole, proxibarbal, proxibutene,proxicromil, proxifezone, proxorphan, proxymetacaine, proxyphylline,prozapine, prucalopride, prulifloxacin, pruvanserin, pseudoephedrine,pumafentrine, pumaprazole, pumitepa, pumosetrag, puromycin, pyrabrom,pyrantel, pyrathiazine, pyrazinamide, pyrazofinin, pyricarbate,pyridarone, pyridinol, pyridofylline, pyridostigmine, pyridoxal,pyridoxamine, pyridoxine, pyrilamine, pyrimethamine, pyrimate,pyrinoline, pyrithione, pyrithyldione, pyritidium, pyritinol,pyrophenindane, pyrovalerone, pyroxamine, pyrrobutamine, pyrrocaine,pyrrolifene, pyrroliphene, pyrrolnitrin, pyrroxane, pyrvinium, pytamine,quadazocine, quadrosilan, quatacaine, quazepam, quazinone, quazodine,quazolast, quetiapine, quifenadine, quiflapon, quillifoline,quilostigmine, quinacainol, quinacillin, quinacrine, quinagolide,quinaldine blue, quinapril, quinaprilat, quinazosin, quibolene,quincarbate, quindecamine, quindonium, quindoxin, quinelorane,quinestradol, quinestrol, quinethazone, quinetolate, quinezamide,quirifamide, quingestanol acetate, quingestrone, quinidine, quinine,quinotolast, quinpirole, quinterenol, quitiofos, quinuclium,quinuptamine, quinupristin, quipazine, quisultazine, rabeprazole,raclopride, ractopamine, radafaxine, rafoxanide, ragaglitazar,ralitoline, raloxifene, raltitrexed, raluridine, ramatroban, ramciclane,ramelteon, ramifenazone, ramipril, ramiprilat, ramixotidine,ramnocligin, ramnoplanin, ramorelix, ramosetron, ranelic acid,ranimustine, ranimycin, ranirestat, ranitidine, ranolaine, rapacuronium,rasagiline, rasburi case, rathyronine, ravuconazole, razaxaban,razinodil, razobazam, razoxane, rebimastat, reboxetine, recainam,reclazepam, regadenoson, reglitazar, rdcovaptan, relomycin, remacemide,remifentanil, remikiren, remiprostol, remoxipride, renaholone,rentiapril, renzapride, repaglinide, reparixin, repinotan, repirinast,repromicin, reproterol, rescimetol, rescinnamine, resequinil, reserpine,resiquimod, resocortol butyrate, resorantel, resorcinol, retapamulin,retelliptine, retigabine, retinol, revaprazan, revatropate, revenast,revipaiin, revizinone, revospirone, ribavirin, riboflavin, riboprine,ribostamuycin, ricasetron, ridazolol, ridogrel, rifabutin, rifalazil,rifametane, rifamexil, rifamide, rifampin, rifapentine, rifaximin,rilapine, rilmakalim, rilmazafone, rilmenidine, rilopirox, rilozarone,rilpovorine, riluzole, rimantadine, rimazolium, rimcazole, rimexolone,rimiterol, rimonabant, rimoprogin, riodipine, rioprostil, ripazepain,ripisartan, risarestat, risedronicacid, risocaine, risotilide,rispenzepine, risperidone, ristianol, ristocetin, ritanserin, ritometan,ritipenem, ritobegron, ritodrine, ritolukast, ritonavir, ritropirronium,ritrosulfan, rivarbxaban, rivastigmine, rivoglitazome, rizatriptan,robalzotan, robenidine, rocastine, rocepafant, rociclovir, rocuronium,rodocaine, rodorubicin, rofecoxib, rofelodine, rofieponide, roflumilast,rogletimide, rokitamycin, rolafagrel, roletamide, rolgamidine,rolicyclidine, rolicyprine, rolipram, rolitetracycline, rolodine,rolziracetam, romazarit, romergoline, romifenone, romifidine, romurtide,ronactolol, ronidazole, ronifibrate, ronipamil, runnel, ropinirole,ropitoin, ropivacaine, ropizine, roquinimex, rosaprostol, rosaramicin,rose bengal, rosiglitazone, rosoxacin, rostafuroxin, rostaporfin,rosterolone, rosuvastatin, rotamicillin, rotigotine, rotoxamine,rotaxate, roxaditnate, roxarsone, roxatidine acetate, roxibolone,roxifiban, roxindole, roxithromycin, roxolonium, roxoperone, rubitecan,ruboxistaurin, rufinamide, rufloxacin, rupatadine, rupintrivir,rutamycin, ruvazone, ruzadolane, sabarubicin, sabcomeline, sabeluzole,sabiporide, saccharin, safingol, safirinol, sagandipine, salacetamide,salafibrate, salantel, salazodine, salazosulfadimidine, salazosulfamide,salazosulfathiazole, salcaprozoic acid, salcolex, salethamide,salflucerine, salicyl alcohol, salicylamide, salicylic acid, salinazid,salinomycin, salmefamol, salmeterol, salmisteine, salnacedin,salprotoside, salsalate, sameridine, samixogrel, sampatrilat,sampirtine, sancycline, sanfetrinem, sanguinarium, saperconazole,saprisartan, sapropterin, saquinavir, sarafloxacin, sarakalim, saralasinsarcolysin, sardomozide, saredutant, saripedent, sarizotati, sarmazenil,samoxicillin, sarpicillin, sarpogrelate, saterinone, satigrel,satranidazole, satraplatin, saviprazole, savoxepin, scopafungin,scopinast, scopolamine, secalciferol, seclazone, secnidazole,secobarbital, securinine, sedecamycin, sedoxantrone, seganserin,segesterone, seglitide, selamectin, selgiline, selfotel, soldenoson,selprazine, sampimod, sematilide, semaxanib, semduramiein, semorphone,semotiadil, semustine, senazodan, seocalcitol, sepazonium, seperidol,sepimostat, seprilose, seproxetine, sequifenadine, seratrodast,serazapine, serfibrate, sergolexole, sermetacin, sertindole, sertraline,setastine, setzindol, setipafant, setiptiline, setoperone, sevitropium,sevopramide, sezalamide, sagoside, sibenadet. Sibopirdine, sibrafiban,sibutramine, siccanin, sifrprazine, siguazodan, silandrone, sildenafil,silibinin, sileristin, silodosin, silodrate, silperisone, siltenzepine,simendan, simetride, simfibrate, simtrazene, simvastatin, sincalide,sinefungin, sinitrodil, sintropium, sipatrigine, siramesine, siratiazem,sirolimus, sisomicin, sitafloxacin, sitalidone, sitamaquine, sitaxentan,sitofibrate, sitoglusoide, siyelestat, soblidotin, sobuzoxane,solabegron, solifenasin, solimastat, solpecainol, solypertine,somatadine, soneclosan, sonepiprazole, sopitazine, sopromidine,soquinolol, sorafenib, soraprazan, sorbinicate, sorbinil, sorivudine,sornidipine, sotalol, soterenol, spaglumic acid, sparfloxacin,sparfosate, sparsomycin, sparteine, spectinomycin, spiclamine,spiperone, spiradoline, spiramide, spiramycin, spirapril, spiraprilat,spirendolol, spirgetine, spirilene, spiriprostil, spirofylline,spirogermaniuni, spiroglumide, spiromustine, spironolactone,spiroplatin, spirorenone, spirotriazine, spiroxasone, spiroxatrine,spiroxepin, spizofurone, sprodiamine, squalamine, squalane,stacofylline, stllimycin, stannsoprfin, stanolone, stanoaolol,stavudine, stearylsufamide, steffimycin, stenbolone, strpronin,stercuroninm, steyaladil, stibamine, stibophen, stilbamidine,stilbazium, stilonium, strimazole, stiripentol, stirocamide, stirofos,streptomycin, streptonicozid, streptonigrin, streptozocin, styramine,subathiazone, subendazole, succinylcholine, succinylsulfathiazole,succisulfone, suclofenide, sucralfate, sucralose, sucrose octaacetate,sucrosufate, sudexanox, sudoxicam, sufenatil, sufotidine, sufugolix,sugammadex sulamserod, sulazepam, sulazuril, sulbattam, sulbenicillin,sulbenox sulbentine, sulbutiamine, suldamine, sulconazole, sulfabenz,sulfabenzamide, sulfabromomethazine, sulfacarbamide, sulfacecole,sulfacetamide, sulfachlorpyridazine, sulfachrysoidinp, sulfaclamide,sulfaclorazole, sulfaclozine, sulfacytine, sulfadiazine,sulfadimethoxine, sulfadoxine, sulfaethidole, sulfaguanidine,sulfaguanole, sulfalene, sulfaloxic acid, sulfamazone, sulfamerazine,sulfameter, sulfamethaziine, sulfamethizole, sulfamethoxazple,sulfamethoxypyridazine, sulfametmidine, sulfametrole sulfamonomethoxine,sulfamoxole, sulfanilamide, sulfanilate, sulfaanitran, sulfaperin,sulfaphenazole, sulfaproxyline, sulfapyridine, sulfaquinoxaline,sulfarsphenamine, sulfasalazine, sulfasomizole, sulfasuccinamide,sulfasymazine, sulfathiazole, sulfathiourea, sulfatolamide,sulfatroxazole, sulfatrozole, sulfazamet, sulfinaolol, sulfinpyrazone,sulfuram, sulfisomidine, sulfisoxazole, sulfobromophthalein,sulfonterol, sulforidazine, sulfosalicylic acid, sulfoxone, sulcrinat,sulindac, sulisatin, sulisobenzone, sulmarin, sulmazole, sulmepride,sulnidazole, sulocarbilate, suloctidil, sulodexide, sulofenur,sulopenem, sulosemide, sulotroban, suloxifen, sulpiride, sulprosal,sulprostone, sultamicillin, sultiame, sultopride, sultosilic acid,sultroponiuni, sulukast, sulverapride, sumacetamol, sumanirole,sumarotene, sumatriptan, sumetizide, sunagrel, suncillin, sunepitron,supidimide, supalast, suproclone, suprofen, suramin, suricamide,suriclone, suritozole, suronacrine, susalimod, suxemerid, suxethonium,suxibuzone, symclosene, synetine, tabilautide, tabimorelin, tacalcitol,tacapenem, tacedinaline, taclamine, tacrine, tacrolimus, tadalafil,tafluposide, taglutamine, tagorizine, talampanel, talampicillin,talaporfin, talastine, talbutal, taleranol, talibegron, talinolol,talipexole, talisomycin, tallimustine, talmetacin, talmetoprim,talnetant, talniflumate, talopram, talsalate, toloximine, talsaclidinc,talsupram, taltirelin, taltobulin, taltrimide, taludipine, talviraline,tameridone, tameticillin, tametraline, tamibarotene, tamitinol,tanolarizine, tamoxifen, tampramine, tamsulosin, tanaproget, tandamine,tandospirone, tandutinib, taniplon, tanomastat, tapentadol, taprizosin,taprostene, tarazepide, tariquindar, tasosartan, tasuldine, taurolidine,tauromustine, tauroselcholic acid, taurosteine, tazadolene, tazanolast,tazarotene, tazasubrate, tazeprofen, tazifylline, taziprinone,tazobactam, tazofelone, tazolol, tazometine, tebanicline, tebatizole,tebipenem, tebufelone, tebuquine, tecadenoson, tecalcet, tecastemizole,teclthiazide, teclozan, tedisamil, tefazoline, tefenperate, teflufazine,tefiutixol, tegafur, tegaserod, teglicar, teicopanin, telavancin,telbivudine, telenzepine, telinavir, telithromycin, telmesteine,telmisartan, teloxantrone, teludipine, temafloxacin, temarotene,tematropium, temazepam, temefos, temelastine, temiverine, temocapril,temocaprilat, temocillin, temodox, temoporfin, temozolomide,temisirolimus, temurtide, tenamfetamine, tenatoprazole, tendamistat,tenidap, tenilapine, teniloxazine, tenilsetam, teniposide, tenivastatin,tenocyclidine, tenofovir, tenofovir disoproxil, tenonitrozole, tenosal,tenosiprol, tenoxicam, tenylidone, teoprantil, teoprolol, tepirindole,tepoxalin, teprenone, teprotide, terazosin, terbequinil, terbinafine,terbogrel, terbucromil, terbufirol, terbuficin, terbuprol, terbutaline,terciprazine, terconazole, terdecamycin, teerestigmine, terfeadine,terfiavoxate, terfuranol, terguride, tetiflunomide, terikalant,terizidone, terlakiren, terlipressin, ternidazole, terodiline,terofenamate, teroxalene, teroxirone, tertatolol, tesaglitazar, tesicam,tesimide, tesimilifene, tesofensine, testolactone, testosterone,tetomilst, tetrabarbital, tetrabenazine, tetracaine, tetracycline,tetrahydrozoline, tetramethrin, tettamisole, tetraxetan, tetrazepam,tetrazolast, tetriprofen, tetrofosmin, tetronasin, tetroquinone,tetroxoprin, tetrydamine, teverelix, texacromil, tezacitabine,tezosentan, thalidomide, thebacon, thenalidine, thenium, thenyldiamine,theobromine, theodrenaline, theofibrate, theophylline, thiabendazole,thiacetarsamide, thialbarbital, thiamazole, thiamine, thiamiprine,thiamphenicol, thamylal, thiazesim, thiazinamium, thiazolsulfone,thiethyperazine, thihexinol ethylbromide, thimerfonate, thimerosal,thiocolchicoside, thioctic acid, thiofuradene, thioguanine,thiohexamide, thioinosine, thiopental, thiophanate, thiopropazate,thioproperazine, thioridazine, thiosalan, thiostrpton, thiotepa,thiotetrabarbital, thiothixene, thiphenamil, thiphencillin, thiram,thonzonium, thonzylamine, thozalinone, threonine, thymocartin,thymoctonan, thymol, thymopentin, thymotrinan, thyromedan, thyropropicacid, thyroxin, tiacrilast, tiadenol, tiafibrate, tiagabine,tiamenidine, tiametomnium, tiamulin, tianafac, tianeptine, tiapamil,tiapirinol, tiapride, tiaprofenic acid, tiaprost, tiaramide, tiazofurin,tiazuril, tiabalosin, tibeglisene, tibenelast, tibenzate, tibezonium,tibolone, tibric acid, tibrofan, ticabesine, ticalopride, ticarbodine,ticarcillin, ticlatone, ticlopidine, ticolubant, ticrynafen,tidembersat, tidiacic acid, tiemonium, tienocarbine, tienopramine,tienoxolol, tifemoxone, tifenazoxide, tiflamizole, tiflorex, tifluadom,tiflucarbine, tiformin, tifurac, tigecycline, tigemonam, tigestol,tigloidine, tilargenine, tiletamine, tilidine, tiliquinol, tilisolol,tilmacoxib, tilmicosin, tilnoprofen, tilomisole, tilorone, tilozepine,tilsuprost, tiludonic acid, timcodar, timefurone, timegadine, timelotem,timepidium, timiperone, timirdine, timobesone acetate, timoilbrate,tiniolol, timonacic, timoprazole, tinabinol, tinazoline, timidazole,tinisulpride, tinofedrine, tinoridine, tiocarlide, tioclomarol,tioconazole, tioctilate, tiodazosin, tiodonium, tiomergine,tiomesterone, tioperidone, tiopinate, tiopronin, tiopropamine,tiospirone, tiotidine, tiotropium, tioxacin, tioxamast, tioxaprofen,tioxidazole, tioxolone, tipentosin, tipepidine, tipetropium, tipifarnib,tipindole, tipranavir, tipredane, tiprenolol, tiprinast, tiprodil,tiprostanide, tiportimod, tiqueside, tiquinamide, tiquizium, tiracizine,tirapazamine, tiratricol, tirilazad, tirofiban, tiropramine, tisartan,tisocalcitate, tisocromide, tisopurine, tisoquone, tivanidazole,tiviciclovir, tivirapine, tixadil, tixanox, tixocortol, tizabrin,tizanidine, tizolemide, tizoprolic acid, tobicillin, toborinone,tobramycin, tocainide, tocamphyl, tocladesine, tocofenoxate,tocofibrate, tocophersolan, todralazine, tofenacin, tofetridine,tofimilast, tofisoline, tofisppam, tolafentrine, tolamolol, tolazamide,tolboxane, tolbutamide, tolvapone, tolciclate, toldimfos, tolfamide,tolfenamic acid, tolgabide, tolimidone, tolindate, toliodium,toliprolol, tolmesoxidd, tometin, tolnaftate, tolnapersine, tolnidamine,toloconium, tolonidine, tolonium, toloxatone, toloxychlorinol, tolpadol,tolpentamide, tolperisone, tolpiprazole, toipronine, tolpropamide,tolpyrramide, tolquinzole, tolrestat, tolterodine, toltrazuril,tolufazepam, tolvaptan, tolycaine, tomeglovir, tomelukast, tomoglumide,tomoxiprole, tonabersat, tonazocine, topilutamide, topiramate,topixantrone, topotecan, toprilidine, topterone, toquizine,torbafylline, torcetrapib, torcitabine, toremifene, toripristone,torsemide, tosagestin, tosifen, tosufioxacin, tosulur, trabecteclin,traboxopine, tracazolate, tradecamide, tralonide, tramadol, tramazoline,trandolapril, trandolaprilat, tranexamic acid, tranilast, transcamide,trantelinium, tranycypromine, trapencaine, trapidil, travoprost,traxanox, traxoprodil, trazitiline, trazium, trazodone, trazolopride,trebenzomine, trecadrine, trecetilide, trefentanil, trelnarizine,treloxinate, trenbolone, trengestone, trenizine, treosulfan,trepibutone, trepipam, trepirium, treprostinil, treptilamine, terquisin,tresperimus, trestolone, trethinium, trethocanoic acid, tretinoin,tretinoin tocoferil, tretoquinol, triacetin, triafungin, triamcinolone,triamcinolone acetonide, triamcinolone benetonide, triamcinolonefuretonide, triampyzine, triamternem triaziquone, triazolam,tribendilol, tribenoside, tribromsalan, tribuzone, tricaprilin,tricetamide, trichlorfon, trichlormethiazide, trichlomethine,triciribine, triclabendazole, triclacetamol, triclazate, triclobisonium,triclocarban, triclodazol, triclofenol, triclofos, triciofyllin,triclonide, triclosan, tricyclamol, tridihexethyl, tridolgosir,trientine, triethylenemelamine, trifenagrel, trifezolac, triflocin,triflubazam, triflumidate, triflomeprazine, trifluperazine,trifluperidol, triflupromazine, triflusal, trifosmin, trigevolol,trihexylpheidyl, triletide, trilostane, trimazosin, trimebutine,trimecain, trimedoxime, trimegestone, trimeperidine, trimeprazine,trimetazidine, trimethadone, trimethamide, trimethaphan, trimethidinium,trimethobenzamide, trimethoprim, trimetozine, trimetrexzate,trimexiline, trimipramine, trimoprostil, trimoxamine, trioxifene,trioxsalen, tripalmitin, tripamide, triparanol, tripelennamine,triplatin, triprolidine, triptorelin, tritoqualine, trixolane,trizoxime, trocimine, troclosene, trodusquemine, trofosfamide,troglitazone, troleandomycin, tromanttadine, tropabazate, tropanserin,tropapride, tropatepine, tropenziline, tropicamide, tropigline,tropirine, tropisetron, tropodifene, troquidazole, trospectomycin,trospium, trovafloxacin, trovirdine, troxacitabine, troxerutin,troxipide, troxolamide, troxonium, troxypyrrolium, truxicurium,truxipicurium, tryparsamide, tubocurarine, tubulozole, tucaresol,tuclazepam, tulathromycin, tulobuterol, tulopafant, turosteride,tuvatidine, tybamate, tylosin, tyinazolin, tyropanoate, tyrosine,tyrothricin, ubenimex, ubidecarenone, ubisindine, ufenamate, utiprazole,uldazepam, ulifloxacin, uliprisnil, umespirone, undecylenic acid,unoprostone, upenazinie, upidosin, uracil, uracil mustard, urapidil,uredepa, uredofos, urefibrate, ursodiol, urulcholic acid, utibapril,utibaprilat, vadocaine, valaciclovir, valconazole, valdecoxib,valdetamide, valdipromide, valethamate, vlaganiciclovir, valine,valnemulin, vlanoctamide, valofane, valomacielovir, valperinol,valproate, vlaproicacid, valpromide, valrocemide, valrubicin, valsartan,valorcitabine, valtrate, vamicamide, vancomycin, vandetanib, vaneprim,vanitiolide, vanoxerine, vanyldisulfamide, vapiprost, vapreotide,vardenfanil, varenicline, varespladib, vatalanib, vatanidipine,vebufloxacin, vecuronium, vedaclidine, vedaprofen, velaresol,velnacrine, venlafaxine, venritidine, verodoline, veralipride,verapamil, verazide, verilopam, verlukast, verofylline, versetamide,verteporfin, vesnarinone, vestipitant, vetrabutine, vidarabine,vigabatrin, vilazodone, vildaglipin, viloxazine, vinbarbital,vinblastine, vinburnine, vincamine, vincanol, vincofos, vinconate,vincristine, vindeburnol, vindesine, vinpidine, vinflunine, vinformide,vinfosiltine, vinglycinate, vinleucinol, vinleurosine, vinmegallate,vinorelbine, vinpocetine, vinpoline, vinrosidine, vintiamol, vintoperol,vintriptol, vinylbital, vinzolidine, viomycin, viprostol, viqualine,viquidil, virginiamycin, viridofulvin, viroxime, visnadine,visnafylline, vofopitant, voglibose, volazocine, volpristin,voriconazole, vorozole, voxergolide, xaliproden, xamoterol, xanomeline,xanoxic acid, xanthinol, xantifibrate, xantocillin, xantofyl palmitate,xemilofiban, xenalipin, xcnazoic acid, xenbucin, xenipentone,xenothiorate, xenygloxal, xcnylhexenicacid, xenylropium, xibenolol,xibornol, xidecaflur, xilobam, ximelagatran, ximoprofen, ximidamine,xinomiline, sipamide, xipranolol, xorphanol, xylamidine, xylazine,xylocoutnarol, xylometazoline, xyloxemine, yohimbic acid, zabicipril,zabiciprilat, zacopride, zafirlukast, zafuleptine, zalcitabine,zalderide, zaleplon, zalospirone, zalitidine, zaltoprofen, zamifenacin,zanamivir, zanapezil, zankiren, zanoterone, zapizolani, zaprinast,zardaverine, zatebradine, zatosetron, zelandopana, zenarestat,zenazocine, zeniplatin, zepastine, zeranol, zetidoline, zidapamide,zidometacin, zidovudine, zifrostilone, zilantel, zilascorb, zileuton,zilpaterol, zimeldine, zimiidoben, zindottine, zindoxifene, zinconazole,zinostatin, zinterol, zinviroxime, zipeprol, ziprsidone, zocainone,zofenopril, zofenoprilat, zoficonazole, zolamine, zolasartan, zolazepam,zolendronic acid, zolenzepine, zolertine, zolimidine, zoliprofen,zolmitriptan, zoloperone, Zolpidem, zomebazam, zomepirac, zometapine,zonampanel, zoniclezole, zoniporide, zonisamide, zopiclone, zopolrestat,zorbamycin, zorubicin, zosuquidar, zotepine, zoticasone, zoxazolamine,zucapsaicin, zuclomiphene, zuclopenthixol, zylofuramine, andcombinations thereof.

In one embodiment, the active pharmaceutical compound includes anysuitable pharmaceutical substance with a half-life of from about 16hours to about 21 hours. In another embodiment, the activepharmaceutical substance has a half-life of from about 16 hours to about21 hours, about 17 hours to about 21 hours, from about 18 hours to about21 hours, from about 19 hours to about 21 hours, from about 20 hours toabout 21 hours, from about 16 hours to about 17 hours, from about 16hours to about 18 hours, from about 16 hours to about 19 hours, fromabout 16 hours to about 20 hours, from about 17 hours to about 18 hours,from about 17 hours to about 19 hours, from about 17 hours to about 20hours, from about 17 hours to about 21 hours, from about 18 hours toabout 19 hours, from about 18 hours to about 20 hours, from about 18hours to about 21 hours, from about 19 hours to about 20 hours, fromabout 19 hours to about 21 hours, or from about 20 hours to about 21hours.

B. Compositions

Exemplary embodiments of the present invention include controlledabsorption pharmaceutical formulations for extended release ofpharmaceutically active compounds. In some embodiments, the controlledrelease dosage form is formulated for oral administration ofpharmaceutically active agent that is suitable for administration topatients that have difficulty swallowing solid oral dosage forms. Infurther embodiments, the controlled absorption pharmaceuticalformulation can be used with acceptable ‘soft food’ for use withpatients that have difficulty swallowing a tablet, capsule or pill. Insome embodiments, the controlled absorption pharmaceutical formulationcan be modified foradministration of the pharmaceutically activecompounds in a gastro-nasal feeding tube or any other “feeding tube”type apparatus where timed release of the pharmaceutically activecompound is desired.

In some embodiments, oral delivery of the controlled absorptionpharmaceutical formulation is preferred. Since the pharmaceuticalcompositions disclosed herein may be delivered by oral administration topatient, including an animal and a human, these compositions may beformulated with an inert diluent or with an assimilable edible carrier,or they may be enclosed in hard- or soft-shell gelatin capsule, or theymay be compressed into tablets, or they may be incorporated directlywith the food of the diet.

In some embodiments, the pharmaceutical composition of the presentinvention may be formulated for parenteral delivery. Alternatively, thepharmaceutical composition may be formulated for nasal, buccal, passivetransdermal, iontophoretic transdermal, electrophoretic transdermal,microneedle transdermal, or skin ablation transdermal delivery.

In one exemplary embodiment, the controlled release pharmaceuticalformulation comprises a particulate composition, said particulatecomposition comprising (a) a core, said core comprising apharmaceutically active substance and a set of one or more drug-bindingpolymers, wherein said pharmaceutically active substance is inreversible association with said set of one or more drug bindingpolymers; and (b) a membrane, said membrane surrounding said core andcomprising a pharmaceutically acceptable film-forming, water insolublepolymer. In one embodiment, the drug-binding polymer comprises methylcellulose. In another embodiment, the pharmaceutically active substanceand the set of one or more drug-binding polymers are present inrespective weight ratio of from about 20:1 to about 1:2. In anotherembodiment, the pharmaceutically active substance and the set of oneormore drug-binding polymers are present in respective weight ratio ofabout 20:1, about 19:1, about 18:1, about 17:1, about 16:1, about 15:1,about 14:1, about 13:1, about 12:1, about 11:1, about 10:1, about 9:1,about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, about2:1, about 19:2, about 17:2, about 15:2, about 13:2, about 11:2, about9:2, about 7:2, about 5:2, about 4:2, about 3:2, or about 2:1.

In one exemplary embodiment, the controlled absorption compositioncomprises naproxen as the pharmaceutically active substance. In anotherexemplary embodiment, the controlled absorption composition comprises anaproxen salt as the pharmaceutically active substance. In a specificembodiment, the controlled absorption composition comprises free acid asthe pharmaceutically active substance. In another specific embodiment,the controlled absorption composition comprises naproxen sodium salt asthe pharmaceutically active substance.

The particles of the compositions for use in accordance with theinvention may be of any desired shape. Exemplary shapes includespheroidal, plates, shards, fibers, cuboidal, sheets, rods, oval,strings, elongated particles, wedges; dists, rectangular, polyhedral,etc. In accordance with the invention it is of advantage if they have aspheriod shape. In the context of the present invention, a spheriodshape is a shape substantially like that of a ball. Examples ofspheroidal shapes include, beads, egg-shaped particles, dodecahedra oricosahedra, which may also have certain irregularities.

In some embodiments, the particles have a median or mean diameter offrom about 0.1 mm to about 0.9 mm. In other embodiments, the averagediameter of particles in the particulate composition is 0.8 mm. Ingeneral, the median or mean diameter of particles in the composition inaccordance with thepresent invention ranges from 0.2 mm to 0.9 mm, from0.3 mm to 0.9 mm, from 0.4 mm to 0.9 mm, from 0.5 mm to 0.9 mm, from 0.6mm to 0.9 mm, from 0.7 mm to 0.9 mm, from 0.8 mm to 0.9 mm, from 0.1 mmto 0.2 mm, from 0.1 mm to 0.3 mm, from 0.1 mm to 0.4 ram, from 0.1 mm to0.5 mm, from 0.1 mm to 0.6 mm, from 0.1 mm to 0.7 mm, from 0.1 mm to 0.8mm, from 0.2 mm to 0.3 mm, from 0.2 mm to 0.4 mm, from 0.2 mm to 0.5 mm,from 0.2 mm to 0.6 mm, from 0.2 mm to 0.7 mm, from 0.2 mm to 0.8 mm,from 0.3 mm to 0.4 mm, from 0.3 mm to 0.5 mm, from 0.3 mm to 0.6 mm,from 0.3 mm to 0.7 mm, from 0.3 mm to 0.8 mm, from 0.4 mm to 0.5 mm,from 0.4 mm to 0.6 mm, from 0.4 mm to 0.7 mm, from 0.4 mm to 0.8 mm,from 0.5 mm to 0.6 mm, from 0.5 mm to 0.7 mm, from 0.5 mm to 0.8 mm,from 0.6 mm to 0.7 mm, or from 0.7 mm to 0.8 mm.

Thus, particle properties can be valuable indicators of quality andperformance of particulate materials in pharmaceutical applications. Inthe case of particle size, several particle size measuring methodsexists, including volume-, weight- and area-based particle sizemeasuring techniques. These particle size measuring methods includelight-based methods, ultrasound, electric field, gravity, andcentrifugation-based methods. Laser diffraction results, for exemple,are reported on a volume basis and so volume mean can be used to definethe central point although the median is more frequently used than themean when using this technique. Particles size distributions disclosedherein were determined by microphotography, area-based particle sizemeasuring technique. Integrating size of the particles, area wasobtained from which the diameters of the particles were calculated.

FIGS. 6 and 7 respectively illustrate particle distributions forexemplary Formulations 2 and 4. As illustrated in these figures aparticdlate composition according to the present invention can comprisesmicroparticles/microparticulates having a range of particle sizes. Apercentage of particles having a given range of particle diameter can becalculated based on these figures according to the following formula:

${{{percentage}\mspace{14mu}{of}\mspace{14mu}{particles}} = \frac{{n(i)} \times 100\%}{n(t)}},$wherein n(i) is the number of particles having a specfic range ofparticle diameter and n(t) is the total particle count in the sample. InFIG. 6, for example, n(t)=(6+15+16+10+3+2+1+5+1)=59, the percentage ofparticles having particle diameter range of 102-207 mm is(6/59)×100%≈10.2%. This calculation can be performed for each of rangeof particle diameter. A similar set of calculations can be carried outfor the particle distribution in FIG. 7 to determine the percentage ofparticles within each range of particle diameters.

Accordingly, in some embodiments of the particulate composition of thepresent invention: about 10% of the particles have a particle diameterof at least about 102 μm but equal or less than about 207; about 35% ofthe particles have a particle diameter of at least about 102 μm butequal or less than about 313; about 62% of the particles have a particlediameter of at least about 102 μm but equal or less than about 419;about 79% of the particles have a particle diameter of at least about102 μm but equal or less than about 525; about 84% of the particles havea particle diameter of at least about 102 μm but equal or less thanabout 631; about 88% of the particles have a particle diameter of atleast about 102 μm but equal or less than about 737; about 89% of theparticles have a particle diameter of at least about 102 μm but equal orless than about 949; about 98% of the particles have a particle diameterof at least about 102 μm but equal or less than about 1055; at leastabout 99% of the particles have a particle diameter of at least about102 μm but equal or less than about 1267.

In some embodiments of the particulate composition of the presentinvention: about 7% of the particles have a particle diameter of atleast about 179 μm but equal or less than about 240 μm; about 14% of theparticles have a particle diameter of at least about 179 μm but equal orless than about 302 μm; about 37% of the particles have a particlediameter of at least about 179 μm but equal or less than about 364 μm;about 53% of the particles have a particle diameter of at least about179 μm but equal or less than about 426 μm; about 74% of the particleshave a particle, diameter of at least about 179 μm but equal or lessthan about 488 μm; about 87% of the particles have a particle diameterof at least about 179 μm but equal or less than about 550 μm; about 90%of the particles have a particle diameter of at least about 179 μm butequal or less than about 612 μm; about 93% of the particles have aparticle diameter of at least about 179 μm but equal or less than abdut674 μm; about 97% of the particleS have a particle diameter of at leastabout 179 μm but equal or less than about 736 μm; and at least about 98%of the particles have a particle diameter of at least about 179 μm butequal or less than about 860 μm.

In some embodiments, a particulate composition in accordance with thepresent invention comprises a particle distribution wherein about 99% ofthe particles have a particle diameter of about 1.267 μm or less. Insome embodiments, said particle size distribution is selected from thegroup consisting of: about 98% of particles having a particle diameterof about 1055 μm or less; about 89% of particles having a particlediameter of about 949 μm or less; about 87% of particles having aparticle diameter of about 737 μm or less; about 84% of particles havinga particle diameter of about 631 μm or less; about 79% of particleshaving a particle diameter of about 525 μm or less; about 62% ofparticles having a particle diameter of about 419 μm or less; about 35%of particles having a particle diameter of about 313 μm or less; andabout 10% of particles having a particle diameter of about 207 μm orless.

In some embodiments, a particulate composition in accordance with thepresent invention comprises a particle distribution wherein about

In one embodiment, a particulate composition according to the presentinvention comprises microparticles/microparticulates having averagediameter of from about 100 μm to about 900 μm. In another embodiment,said particulate composition comprises microparticles/microparticulateshaving average diamter selected from the group consisting of: from 100μm to about 150 μm; from about 150 μm to about 200 μm; from about 200 μmto about 250 μm; from about 250 μm to about 360 μm; from about 300 μm toabout 350 μm; from about 350 μm to about 400 μm; from about 400 μm toabout 450 μm; from about 450 μm to about 500 μm; from about 500 μm toabout 550 μm; from about 550 μm to about 600 μm; from about 600 μm toabout 650 μm; from about 650 μm to about 700 μm; from about 700 μm toabout 750 μm; from about 750 μm to about 800 μm; from about 800 μm toabout 850 μm; from about 850 μm to about 900 μm; from about 150 μm toabout 200 μm; from about 200 μm to about 250 μm; from about 250 μm toabout 300 μm; from about 300 μm to about 350 μm; from about 350 μm toabout 400 μm; from about 400 μm to about 450 μm; from about 450 μm toabout 500 μm; from about 500 μm to about 550 μm; from about 550 μm toabout 600 μm; from about 600 μm to about 650 μm; from about 650 μm toabout 700 μm; from about 700 μm to about 750 μm; from about 750 μm toabout 800 μm; from about 800 μm to about 850 μm from about 200 μm toabout 250 μm; from about 250 μm to about 300 μm; from about 300 μm toabout 350 μm; from about 350 μm to about 400 μm; from about 400 μm toabout 450 μm from about 450 μm to about 500 μm; from about 500 μm toabout 550 μm; from about 550 μm to about 600 μm; from about 600 μm toabout 650 μm; from about 650 μm to about 700 μm from about 700 μm toabout 750 μm; from about 750 μm to about 800 μm; from about 250 μmtoabout 300 μm; from about 300 μm to about 350 μm; from about 350 μm toabout 400 μmfrom about 400 μm to about 450 μm; from about 450 μm toabout 500 μm; from about 500 μm to about 550 μm; from about 550 μm toabout 600 μm; from about 600 μm to about 650 μm; from about 650 μm toabout 700 μm; from about 700 μm to about 750 μm; from about 300 μm toabout 350 μm; from to about 350 μm to about 400 μm; from to about 400 μmto about 450 μm; from to about 450 μm to about 500 μm; from to about 350μm to about 400 μm; from to about 400 μm to about 450 μm; from to about450 μm to about 500 μm and combinations thereof.

In another embodiment, a particulate composition according to thepresent invention has a particle size distribution wherein at least 98%of the particles have a di amter of about 860 μm or less. In anotherembodiment, said particle size distribution is selected from the groupconsisting of: about 97% of particles having a particle diameter ofabout 798 μm or less; about 93% of particles having a particle diameterof about 736 μm or less; about 92% of particles having a particlediameter of about 674 μm or less; about 90% of particles having aparticle diameter of about 612 μm or less; about 87% of particles havinga particle diameter of about 550 μm or less; about 74% of particleshaving a particle diameter of about 488 μm or less; about 53% ofparticles having a particle diameter of about 426 μm or less; about 37%of particles having a particle diameter of about 364 μm or less; about14% of particles having a particle diameter of about 302 μm or less;about and 7% of particles having a particle diameter of about 240 μm orless.

In another embodiment, a particulate composition according to thepresent invention has a particle size distribution wherein the smallestparticle has a diatheter of at least 102 μm

As for irregularly shaped particles, the recited dimension ranges mayrepresent the length of the greatest or smallest dimension of theparticle. As examples, the particles can be pin shaped, with taperedends having an average diameter of from about 0.2 mm to about 0.8 mm. Aswill be appreciated by one of skill in the art, the maximum particlesize will depend in part on whether the composition will effectsatisfactory controlled release of the active pharmaceutical substance.

In some exemplary embodiments, the controlled absorption compositioncomprises a sufficient quantity of a rapid release form of thepharmaceutically active substance to ensure prompt achievement ofdesired plasma levels of the pharmaceutically active substance togetherwith a sustained release form of the pharmaceutically active, substancefor prolonged biological effects. In one embodiment, the controlledabsorption composition comprises rapid and prolonged release componentsthat preferably have a dissolution rate which when measured in: a type 1dissolution basket apparatus according to U.S. Pharmacopoeia XXII inphosphate buffer at pH 7.2 and at 75 r.p.m. substantially corresponds tothe following dissolution pattern: (a) from 15 to 50% of the totalpharmaceutically active substance is released after 0.5 hourS ofmeasurement in said apparatus; (b) from 25 to 75% of the totalpharmaceutically active substance is released after 1 hour ofmeasurement in said apparatus; (c) not less than 65% of the totalpharmaceutically active substance is released after 4 hours ofmeasurement in said apparatus. In one embodiment, the pharmaceuticallyactive substance is naproxen sodium salt. In another embodiment, thepharmaceutically active substance is naproxen free acid. In oneembodiment, the controlled absorption composition adapted to oraladministration of naproxen, and including a sufficient quantity of arapid release form of naproxen to ensure prompt achievement ofanalgesically effective blood levels together with the prolonged effectsdescribed above.

In one embodiment, the twice a day administration is reduced to once aday administration by extending the release profiling by 2, hours or 2-4hours, or 3-8 hours while still maintaining efficacious blood levels ofthe pharmaceutically active substance.

In another embodiment, the controlled absorption composition comprisesrapid and prolonged release components such that when its dissolutionrate is measured in vitro in a type 2 dissolution paddle apparatusaccording to U.S. Pharmacopoeia XXII in phosphate buffer at pH 7.4 andat 50 r.p.m. the dissolution rate substantially corresponds to thefollowing dissolution pattern: (a) from 25% to 60% of the totalpharmaceutically active substance is released after 0.5 hours ofmeasurement in said apparatus; (b) from 35% to 75% of the totalpharmaceutically active substance is released after 1 hour ofmeasurement in said apparatus; and (c) not less than 65% of the totalpharmaceutically active, substance is released after 4 hours ofmeasurement in said apparatus. In one embodiment, the pharmaceuticallyactive substance is naproxen sodium salt. In another embodiment, thepharmaceutically active substance is naproxen free acid. In one,embodiment, the controlled absorption composition adapted to oraladministration of naproxen, and including a sufficient quantity of arapid release form of naproxen to ensure prompt achievement ofanalgesically effective blood levels together with the prolonged effectsdescribed above.

While exemplary embodiments described herein use naproxen sodium toillustrate aspects of the present invention, it will be understood bythose skilled in the art that any suitable pharmaceutically activecompound can be used. Examples of pharmaceutically active compounds thatmay be used with the composition of the present invention are given inSection A above.

In one embodiment, a naproxen formulation for oral administrationcomprises particulates as described herein, said formulation including asufficient quantity of a rapid release form of naproxen to ensure promptachievement of analgesically effective blood levels together with asustained release form of naproxen for prolonged analgesic effects. Inan embodiment, the formulation comprises rapid and prolonged releasecomponents, preferably having a dissolution rate which when measured ina type 1 dissolution basket apparatus according to U.S. PharmacopoeiaXXII in phosphate buffer at pH 7.2 and at 75 r.p.m. substantiallycorresponds to the following dissolution pattern: (a) from 15 to 50% ofthe total naproxen is released after 0.5 hours of measurement in saidapparatus; (b) from 25 to 75% of the total naproxen is released after 1hour of measurement in said apparatus; (c) not less than 65% of thetotal naproxen is released after 4 hours of measurement in saidapparatus.

In another embodiment, the formulation of naproxen comprises rapid andprolonged release components. Preferably, when dissolution rate of thenaproxen formulation is measured, in vitro in a type 2 dissolutionpaddle apparatus according to U.S. Pharmacopoeia XXII in phosphatebuffer at pH 7.4 and at 50 r.p.m, the dissolution rate substantiallycorresponds to the following dissolution pattern: (a) from 25 to 60% ofthe total naprcixen is released after 0.5 hourS of measurement in saidapparatus; (b) from 35 to 75% of the total naproxen is released after 1hour of measurement in said apparatus; and (c) not less than 65% of thetotal naproxen is released after 4 hours of measurement in saidapparatus.

In another preferred embodiment, the set one or more drug-bindingpolymers are selected from the group comprising: methyl cellulose, ethylcellulose, carboxy methylcellulose, diethylaminoethyl cellulose andother suitable matrixes which have the ability to bind thepharmaceutical agent through ionic attraction, or weak hydrogen bonding.

In a further embodiment, the core of the particulate composition of thepresent invention can contain a lubricant. In one embodiment, thelubricant comprises sodium stearate, magnesium, stearate, stearic acid,talc or combinations thereof. Generally, the pharmaceutically activeagent and the lubricant are preferably present in a weight ratio of fromabout 10:1 to about 200:1. In another embodiment, the pharmaceuticallyactive agent and the lubricant are preferably present in a weight ratioof about 11:1, about 12:1, about 13:1, about 14:1, about 15:1, about16:1, about 17:1, about 18:1, about 19:1, about 20:1, about 21:1, about22:1, about 23:1, about 24:1, about 25:1, about 26:1, about 27:1, about28:1, about 29:1, about 30:1, about 31:1, about 32:1, about 33:1, about34:1, about 35:1, about 36:1, about 37:1, about 38:1, about 39:1, about40:1, about 41:1, about 42:1, about 43:1, about 44:1, about 45:1, about46:1, about, 47:1, about 48:1, about 49:1, about 50:1, about 51:1, about52:1, about 53:1, about 54:1, about 55:1, about 56:1, about 57:1, about58:1, about 59:1, about 60:1, about 61:1, about 62:1, about 63:1, about64:1, about 65:1, about 66:1, about 67:1, about 68:1, about 69:1, about70:1, about 71:1, about 72:1, about 73:1, about 74:1, about 75:1, about76:1, about 77:1, about 78:1, about 79:1, about 80:1, about 81:1, about82:1, about 83:1, about 84:1, about 85:1, about 86:1, about 87:1, about88:1, about 89:1, about 90:1, about 91:1, about 92:1, about 93:1, about94:1, about 951, about 96:1, about 97:1, about 98:1, about 99:1; about100:1, about 101:1, about 102:1, about 103:1, about 104:1, about 105:1,about 106:1, about 107:1, about 108:1, about 109:1, about 110:1, about111:1, about 112:1, about 113:1, about 114:1, about 115:1, about 116:1,about 117:1, about 118:1, about 119:1, about 120:1, about 121:1, about122:1, about 123:1, about 124:1, about 125:1, about 126:1, about 127:1,about 128:1, about 129:1, about 130:1, about 131:1, about 132:1, about133:1, about 134:1, about 135:1, about 136:1, about 137:1, about 138:1,about 139:1, about 140:1, about 141:1, about 142:1, about 143:1, about144:1, about 145:1, about 146:1, about 147:1, about 148:1, about 149:1,about 150:1, about 151:1, about 152:1, about 153:1, about 154:1, about155:1, about 156:1, about 157:1, about 158:1, about 159:1, about 160:1,about 161:1, about 162:1, about 163:1, about 164:1, about 165:1, about166:1, about 167:1, about 168:1, about 169:1, about 170:1, about 171:1,about 172:1, about 173:1, about 174:1, about 175:1, about 176:1, about177:1, about 178:1, about 179:1, about 180:1, about 181:1, about 182:1,about 18:3:1, about 184:1, about 185:1, about 186:1, about 187:1, about188:1, about 189:1, about 190:1, about 191:1, about 192:1, about 191:1,about 194:1, about 195:1, about 196:1, about 197:1, about 198:1, about199:1, or about 200:1.

The membrane forming polymeric material suitable for use in the presentinvention may be rapidly soluble in water or insoluble in water orfreely permeable to naproxen and water.

As used herein, the term water soluble polymer includes polymers whichare freely permeable to water.

As used herein, the term water insoluble polymer includes polymers whichare slightly permeable to water.

In some embodiments, the membrane forming polymeric material preferablyconsists solely of a water insoluble polymer or a polymer which isslightly permeable to water and aqueous solutions of thepharmaceutically active substance, including aqueous solutions ofnaproxen. In alternative embodiments, the membrane forming polymericmaterial may consist solely of a water soluble polymer or a polymerwhich is freely permeable to aqueous solutions of naproxen and water.

In some embodiments, the polymeric material of the core may include acombination of a water insoluble polymer with a water soluble polymer.In some embodiments, the ratio of water soluble/freely permeable towater insoluble/slightly permeable polymer is determined by theparticular combination of polymers selected.

In one embodiment, the water soluble polymer is selected from the groupconsisting polyvinyl alcohol, polyvinylpyrrolidone, methyl cellulose,hydroxypropyl cellulose, ethyl cellulose, agar, carrageenan, xanthan,hydroxypropylmethyl cellulose or polyethylene glycol and combinationsthereof. In a preferred embodiment, the water soluble polymer isethycellulose.

In some embodiments, the water insoluble polymer of the core is selectedfrom the group consisting of ethylcellulose, cellulose acetate,cellulose propionate (lower, medium or higher molecular weight),cellulose acetate propionate, cellulose acetate butyrate, celluloseacetate phthalate, cellulose triacetate, poly(methyl methacrylate),poly(ethyl methacrylate), poly(butyl methacrylate), poly(isobutylmethacrylate), poly(hexyl methacrylate), poly(isodecyl methacrylate),poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methylacrylate), poly(isopropyl acrylate), poly(isobutyl acrylate),poly(octadecyl acrylate), poly(ethylene), poly(ethylene) low density,poly(ethylene) high density, poly(propylene), poly(ethylene oxide),poly(ethylene terephthalate), poly(vinyl isobutyl ether), polyvinylacetate), poly(vinyl chloride) or polyurethane and combinations thereof.

In an embodiment, the water insoluble polymer of the core may comprisenaturally occurring polymers and/or resins. In a preferred embodiment,the water insoluble, naturally occurring polymers include shellac,chitosan, gum juniper and combinations thereof.

In one embodiment, a suitable polymer which is slightly permeable toexemplary pharmaceutically active substances, including naproxen, andwater is a polymer sold under the Trade Mark EUDRAGIT RS or a polymerwhose permeability is pH dependent and sold under the Trade MarkEUDRAGIT L, EUDRAGIT S or EUDRAGIT E. In a preferred embodiment, theslightly permeable polymers include of the categories EUDRAGIT RS andEUDRAGIT L and a combination thereof.

EUDRAGIT polymers are polymeric lacquer substances based on acrylatesand/or methacrylates. The polymeric materials sold under theTrade MarksEUDRAGIT RL and EUDRAGIT RS are acrylic resins comprising copolymers ofacrylic and methacrylic acid esters with a low content of quaiernaryammonium groups and are described in the “EUDRAGIT” brochureof Messrs.Rohn Pharma GmbH (1985) wherein detailed physical-chemical data of theseproducts is given. The ammonium groups are present as salts and giverise to the permeability of the lacquer films. EUDRAGIT RL and RS arefreely permeable (RL) or slightly permeable (RS), respectively,independent of pH.

EUDRAGIT L is an anionic polymer synthesized from methacrylic acid andmethacrylic acid methyl ester. It is insoluble in acids and pure water.It becomes soluble in a neutral to weakly alkaline milieu by formingsalts with alkalis. The permeability of EUDRAGIT L is pH dependent.Above pH 5.0, the polymer becomes increasingly permeable. EUDRAGIT L isdescribed in the “EUDRAGIT L” brochure of Messrs. Rohn Pharma GmbH(1986) wherein detailed physical-chemical data of the product is given.

In an exemplary composition, naproxen and binding polymer are blended toform a homogenous powder. In some preferred embodiments, the naproxencomponent and binding polymer component are present in a weight ratio offrom about 20:1 to about 1:2. In some preferred embodiments, thenaproxen component and binding polymer component are present in a weightratio of from about 6:1 to 1:1. In one embodiment, the blend may bepassed through an appropriate mesh screen using a milling machine.

In a further embodiment, the core may optionally contain a lubricant. Inone embodiment, the pharmaceutically active substance, includingnaproxen, and the lubricant are in a weight ratio ranging from about50:1 to about 5:1. In another embodiment, the weight ratio of thepharmaceutically active substance, including naproxen, to the lubricantis about 50:1, about 49:1, about 48:1, about 47:1, about 46:1, about45:1, about 44:1, about 43:1, about 42:1, about 41:1, about 40:1, about39:1, about 38:1; about 37:1, about 36:1, about 35:1, about 34:1, about33:1, about 32:1, about 31:1, about 30:1, about 29:1, about 28:1, about27:1, about 26:1, about 25:1, about 24:1, about 23:1, about 22:1, about2.1:1, about 20:1, about 19:1, about 18:1, about 17:1, about 16:1, about15:1, about 14:1, about 13:1, about 12:1, about 11:1, about 10:1, about9:1, about 8:1, about 7:1, about 6:1, or about 5:1.

In some, preferred etnbodirnents, the coating materials includesolutions/suspensions of the polymers cited for use in the applicationof the powder blend to the central cores in a suitable organic/aqueouscarrier medium.

In one embodiment, the membrane of the film-forming polymer or mixtureof polymers surrounding the core preferably has a proportion of apolymer which is slightly permeable to the pharmaceutically activesubstance, including naproxen, and water and optionally a proportion ofa water permeable polymer, the ratio of slightly water permeable towater permeable polymer being determined by the inherent permeabilitycharacteristics of the polymer selected.

In some embodiments, the membrane of the film-forming polymer or mixtureof polymers surrounding the core preferably may comprise a proportion ofa polymer which iswater insoluble and a proportion of a polymer which iswater soluble, the ratio of the water insoluble polymer to the watersoluble polymer being determined by the inherent permeability of therespective polymers.

In general, the ratio of water insoluble/slightly permeable polymers towater soluble/permeable polymers ranges from about 1:5 to about 50:1. Insome embodiments, the ration ranges from about 1:2 to about 20:1. In oneembodiment, the ratio is about 50:1, about 49:1, about 48:1, about 47:1,about 46:1, about, 45:1, about 44:1, about 43:1, about 42:1, about 41:1,about 40:1, about 39:1, about 38:1, about 37:1, about 36:1, about 35:1,about 34:1, about 33:1, about 32:1, about 31:1, about 30:1, about 29:1,about 28:1, about 27:1, about 26:1, about 25:1, about 24:1, about 23:1,about 22:1, about 21:1, about 20:1, about 19:1, about 18:1, about 17:1,about 16:1, about 15:1, about 14:1, about 13:1, about 12:1, about 11:1,about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, or about 5:1. Inanother embodiment, the ratio is about 20:1, about 19:1, about 18:1,about 17:1, about 16:1, about 15:1, about 14:1, about 13:1, about 12:1,about 11:1, about 10:1, about 9:1, about 8:1, about 7:1, about 6:1,about 5:1, about 4:1, about 3:1, or about 2:1. In yet anotherembodiment, the ratio is about [0001] about 19:2, about 17:2, about15:2, about 13:2, about 11:2, about 9:2, about 7:2, about 5:2, or about3:2. Examples of each of these types of polymer are described above.

The water insoluble polymer of the membrane may also comprise naturallyoccurring polymerS or resins. Suitable water insoluble, naturallyoccurring polymers include, shellac, chitosan, gum juniper andcombinations thereof.

The membrane of the film-forming polymer or mixture of polymerssurrounding the core may be built up by applying a plurality of coats ofmembrane polymer solution or suspension to the core. In someembodiments, the membrane solution or suspension contains the polymer(s)dissolved or suspended, respectively, in a suitable aqueous or organicsolvent or mixture of solvents: In one embodiment, said organic solventsare selected from the group consiting of ethanol, ethylene bromide,butanol, acetone, chloroform, 2-ethylhexanol, methyl ethyl ketone,ethylene chloride, isobutanol, glycerol, methyl isobutyl ketone,dichloromethane, isopropanol, methyl isopropyl ketone,tetrachloroethylene, methanol, mesityl oxide, carbon tetrachloride,propanol, trichloroethylene, propylene glycol, 1,4-dioxane, butyl ether,dimethylformamide, ethyl ether, diisopropyl ether, dimethyl sulfoxide,tetrahydrofuran, tert-butyl methyl ether, pyridyne, acetonitrile, ethylacetate, cyclohexane, toluene, hexane, xylene, other suitable solvents,and combinations thereof. In another embodiment, said aqueous solventsinclude water, water buffered to a specific pH with phosphate orcarbonate ions, and combinations of aqueous and one or more organicsolvents.

The particulate cores in accordance with the present invention areformulated with sustained release characteristics allowing a continuoussupply of the pharmaceutically active substance, including naproxen, tobe maintained in the plasma to achieve a prolonged biological effect,including a prolonged analgesic effect in the case of naproxen. Onadministration of the pharmaceutical formulations in accordance with thepresent invention, including naproxen formulations, the formulation,preferably a particulate, is combined with a soft food, ingested,whereby ingested composition dissociates over time, releasing thepharmaceutically active substance, e.g. naproxen, over a wide area ofthe GI tract. In this way, the number of gastrointestinal absorptionsites is increased, minimizing the occurrence of adverse GI effectsoften associated with the administration the pharmaceutically activesubstances, including NSAID's, and in particulars naproxen. Thecompositions in accordance with the present invention, includingnaproxen particulate formulation, therefore are ideally suited to aonce-daily dosage regimen having the potential for fewer associatedadverse GI effects.

III. EXAMPLES

The Examples that follow are illustrative of comparators and embodimentsof the invention, and various uses thereof. They are set forth forexplanatory purposes only, and are not to be taken as limiting theinvention.

The internal core composed of Naproxen (or a suitable salt) and thepolymeric matrix may be formed by the following procedures. FolloWingcreation of the internal core, the cores were coated with variouspolymers with limited water and pharmaceutically active organic moleculesolubility. The formation of the “sprinkle formulation” is detailed for5 separate formulations below:

Formulation 1

Methocel (20 g) and Naproxen sodium (44 g) were blended for 10 minutesin Kitchenaid mixer (Model KSM103) set at 25 RPMs at ambienttemperature.

The resultant blend was transferred to fluid bed granulator (Fluid AirFluid Bed 2 L granulator) set for top spray granulation. The granulationsolution (Surelease K-L-7 19040 clear) was diluted to contain 20%solids. The bed was fluidized for 5 minutes prior to beginning thespraying. The Surelease was sprayed at a rate of 5 g per minute with thebed temperature maintained at 30-35 C while coating was being applied.Granulation continued until all granulation was consumed. Thegranulation was then left in granulator for 2 hrs at 40° C. with the bedfluidized to allow curing of the Surelease.

Formulation 2

Methocel (56 g) and Naproxen sodium (44 g) were blended for 10 minutesin a Kitchenaid mixer (Model KLM109) set at 25 RPMs at ambienttemperature.

The resultant blend was transferred to fluid bed granulator (Fluid AirFluid Bed 2 L granulator) set for top spray granulation. The granulationsolution (Surelease K-L-7 19040 clear) was diluted to contain 20%solids. The bed was fluidized for 5 minutes prior to beginning thespraying. The Surelease was sprayed at a rate of 5 g per minute with thebed temperature maintained at 30-35 C while coating was being applied.Granulation continued until all granulation was consumed. Thegranulation was then left in granulator for 2 hrs at 40° C. with the bedfluidized to allow curing of the Surelease.

Formulation 3

Avocel (17 g) and Naproxen sodium (53 g) were blended for 10 minutes ina Kitchenaid mixer (Model KLM103) set at 25 RPMs at ambient temperature.

The resultant blend was transferred to fluid bed granulator (Fluid AirFluid Bed 2 L granulator) set for top spray granulation. The granulationsolution (Eudragit RL 30 D) was diluted to contain 20% solids. The bedwas fluidized for 5 minutes prior to solution spray begins. Solution wassprayed at a rate of 15 g per minute with the bed temperature maintainedat 30-35° C. while coating was being applied. Granulation continueduntil all granulation was consumed. The granulation was then left ingranulator for 2 hrs at 40° C. with the bed fluidized to allow curing ofthe Eudragit RL 30 D.

Formulation 4

Prosolv HD90 (25 g), a silicified high-density microcrystallinecellulose composed of 98% microcrystalline cellulose and 2% colloidalsilicon dioxide, and Naproxen sodium (58.3 g) are blended for 10 minutesin a Kitchenaid mixer (Model KLM103) set at 25 RPMs at ambienttemperature.

The resultant blend was transferred to fluid bed granulator (Fluid AirFluid Bed 2 L granulator) set for top spray granulation. The granulationsolution (Eudragit NE 30 D) was diluted to contain 20% solids. The bedwas fluidized for 5 minutes prior to solution spray begins. Solution wassprayed at a rate of 15 g per minute with the bed temperature maintainedat 20-25° C. while coating Was being applied. Granulation continueduntil all granulation was consumed. The granulation was then left ingranulator for 2 hrs at 40° C. with the bed fluidized to allow curing ofthe Eudragit NE30D.

Formulation 5

Prosolv HD90 (20 g), a silicified high-density microcrystallinecellulose composed of 98% microcrystalline cellulose and 2% colloidalsilicon dioxide, and Naproxen sodium (58 g) are blended for 10 minutesin a Kitchenaid mixer (Model KLM103) set at 25 RPMs at ambienttemperature.

The resultant blend was transferred to fluid bed granulator (Fluid AirFluid Bed 2 L granulator) set for top spray granulation. The granulationsolution (Eudragit NE 30 D) was diluted to contain 20% solids. The bedwas fluidized for 5 minutes prior to solution spray begins. Solution wassprayed at a rate of 15 g per minute with the bed temperature maintainedat 20-25° C. while coating was being applied. Granulation continueduntil all granulation was consumed. The granulation was then left ingranulator for 2 hrs at 40° C. with the bed fluidized to allow curing ofthe Eudragit NE30D.

The finished particulates were dried to evaporate all solvents prior toperforming the dissolution test. Following curing, the resultantsprinkle formulations were assayed to determine the naproxen releaserate from the “sprinkles.” Dissolution testing was performed on thegranulations using Elan's Naprelan 375 mg tablet procedure no. 5000000.The testing proceeded as measured in a type 1 dissolution basketapparatus according to U.S. Pharmacopoeia XXII in phosphate buffer at pH7.2 and at 75 r.p.m. In order to keep the granulation in the testbaskets during the dissolution test granulation samples with a particlesize between 425 and 600 μm in diameter.

IV. FIGURES

The accompanying figures are graphs of the percent naproxen releasedwhen tested by the method of the U.S. Pharmacopaeia XXII Basket methodin phosphate buffer at pH 7.2 and at 75 r.p.m. versus time (hours) for anaproxen formulation according to the present invention relative to tworeference naproxen formulations. The naproxen sodium was quantitativelydetermined using u.v. spectrophotometry at 331 nm.

These data indicate that micro granules incorporating naproxen into thecore, when coated with a suitable membrane forming polymer has a releaseprofile which would provide suitable blood concentrations sufficient toproduce the desired analgesic and anti-inflammatory effect which wouldbe comparable to a time release tablet for once or twice a dayadministration. This profile is achieved by the combination of themembrane forming polymer coating the internal pharmaceutically activechemical bound to a polymer.

FIGS. 1 and 2 demonstrate the drug-binding properties of Methocel withrespect to preventing the immediate release of naproxen from theparticles. FIGS. 3-4 demonstrate that Avocet and Prosolv HD90, asilicified high-density microcrystalline cellulose composed of 98%microcrystalline cellulose and 2% colloidal silicon dioxide, both haveappropriate/suitable drug-binding properties matched to releaseanappropriate/suitable amount of naproxen sufficient to provide for asustained release.

The Surelease coating was also found to have an unpleasant texture inthe mouth when formulated as a 425 and 600 μm in diameter particle.

Although Formulation 3 provided an extended release dissolution profile,Formulation 3 did not release enough naproxen to provide for analgesiaand anti-inflammatory response in hours 1-3.

Formulations 4 and 5 provided early release and continued release ofnaproxen for the 4 hours of the test period. In addition, theformulation was of the correct size, for example, having particle sizedistribution of from about 105 μm to about 900 μm, and texture toprovide for a satisfactory formulation.

In order to provide evidence that particle size by itself/alone did notinfluence naproxen release, the diameter of particles of a formulationwhich did provide controlled release over 4 hours (Formulation 4) wascompared to the diameter of particles of a formulation which providedinstant release over 4 hours (Formulation 2). Particles size wasdetermined by microphotography. The measured size (area) of theparticles was integrated to obtain area from which the diameters of theparticles were calculated. Selection of particles for analysis wasrandomized.

When particles for each of the formulations were examined, a sample ofthe particles from Formulation 4 had fewer “fines” or particles lessthan 179 μm in diameter while the particles from Formulation 2 exhibiteda greater number of “fines” or particles less than 100 μm in diameter.Table 1 below describes the average particle size and number of finesfor each of the formulations.

TABLE 1 Naproxen Na Formulations Particle Size Particle DiameterFormulation Mean ± SD (n) Fines Present in Sample #2 435 ± 256 (58) 435particles < 100 μm in diameter #4 420 ± 133 (70)  75 particles < 179 μmin diameter

The particle size distribution for Formulation 2 exhibits a wider rangeof particle sizes as well as more “fines” present in the sample as aproportion of the total number of particles examined (FIG. 6). Theparticle distribution for Formulation 4 exhibits a tighter range ofparticle sizes as well as fewer “fines” present in the sample as aproportion of the total number of particles examined (FIG. 7).

While there may exist particle size contribution to dissolution, it isclear that Formulation 4 exhibits better control of the physicalcharacteristics (particle size) and control of the release of naproxenNa over 4 hours. Formulation 2 exhibits greater instant release, but itis also clear that since most if not all the naproxen Na is releasewithin 2 hours, almost all of the particles (irrespective of their size)release their naproxen Na, indicating that the composition and internalstructure of the particles plays a significant role in the naproxen Narelease characteristics as opposed to only size.

Preferred embodiments of this invention are described herein, includingthe best mode known to the inventors for carrying out the invention.Variations of those preferred embodiments may become apparent to thoseof ordinary skill in the art upon reading the foregoing description. Theinventors expect skilled artisans to employ such variations asappropriate, and the inventors intend for the invention to be practicedotherwise than as specifically described herein. Accordingly, thisinvention includes all modifications and equivalents of the subjectmatter recited in the claims appended hereto as permitted by applicablelaw. Moreover, any combination of the above-described elements in allpossible variations thereof is encompassed by the invention unlessotherwise indicated herein or otherwise clearly contradicted by context.

The invention claimed is:
 1. A method of treating pain in a patient inneed thereof comprising a step of administering to the patient aparticulate composition comprising (a) a biologically active core, saidbiologically active core comprising (i) naproxen, a pharmaceuticallyacceptable salt of said naproxen, or a combination thereof and (ii) adrug binding polymer comprising a silicified high densitymicrocrystalline cellulose composed of 98% microcrystalline celluloseand 2% colloidal silicon dioxide, wherein said naproxen, saidpharmaceutically acceptable salt of said naproxen, or said combinationthereof is in reversible association with said drug binding polymer andin a weight ratio therewith of from about 20:1 to about 1:2; and (b) acoat, said coat comprising a membrane-forming polymer, saidmembrane-forming polymer comprising ethylcellulose and surrounding saidbiologically active core, wherein the particulate composition comprisesmicroparticles/microparticulates having average diameter of from about100 μm to about 900 μm; wherein the particulate composition has adissolution rate which when measured in a type 1 dissolution basketapparatus according to U.S. Pharmacopoeia XXII in phosphate buffer at pH7.2 and at 75 r.p.m. corresponds to the following dissolution pattern(1) from 15 to 50% of the total amount of said naproxen, saidpharmaceutically acceptable salt of said naproxen, or said combinationthereof is released after 0.5 hours of measurement in said apparatus;(2) from 25 to 75% of the total amount of said naproxen, saidpharmaceutically acceptable salt of said naproxen, or said combinationthereof is released after 1 hour of measurement in said apparatus; and(3) not less than 65% of the total amount of said naproxen, saidpharmaceutically acceptable salt of said naproxen, or said combinationthereof is released after 4 hours of measurement in said apparatus. 2.The method of claim 1, wherein the patient has difficulty swallowingsolids.
 3. The method of claim 1, wherein the particulate composition isadministered to the patient together with soft food.
 4. The method ofclaim 1, wherein the biologically active core further comprises a set ofone or more drug binding polymers selected from the group consisting ofcellulose acetate, cellulose propionate, cellulose acetate propionate,cellulose acetate butyrate, cellulose acetate phthalate, cellulosetriacetate, poly(methyl methacrylate), poly(ethyl methacrylate),poly(butyl methacrylate), poly(isobutyl methacrylate), poly(hexylmethacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate),poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropylacrylate), poly(isobutyl acrylate), poly(octadecyl acrylate),poly(ethylene), poly(ethylene) low density, poly(ethylene) high density,poly(propylene), poly(ethylene oxide), poly(ethylene terephthalate),poly(vinyl isobutyl ether), poly(vinyl acetate), poly(vinyl chloride)and polyurethane and combinations thereof.
 5. The method of claim 1,wherein said reversible association between said naproxen, saidpharmaceutically acceptable salt of said naproxen, or said combinationthereof and said drug binding polymer comprises chemical bonding, ionicbonding, complexation, van der Waals interaction, hydrogen bonding, orcombinations thereof.
 6. The method of claim 1, wherein the drug bindingpolymers is insoluble in water.
 7. The method of claim 1, wherein saidcoat further comprises a water-insoluble, water-permeable polymercapable of retarding drug release.
 8. The method of claim 1, whereinsaid biologically active core comprises a powder, said powder comprisingparticles of said naproxen, said pharmaceutically acceptable salt ofsaid naproxen, or said combination thereof mixed with particles of saiddrug binding polymer.
 9. The method of claim 4, wherein saidbiologically active core comprises a powder, said powder comprisingparticles of said naproxen, said pharmaceutically acceptable salt ofsaid naproxen, or said combination thereof mixed with particles of saidset of one or more drug binding polymers, wherein said set of one ormore drug binding polymers comprises at least one pharmaceuticallyacceptable water insoluble polymer.
 10. The method of claim 1, whereinthe composition is a once daily solid controlled-release oral dosageform.
 11. The method of claim 1, wherein the composition is a twice aday solid controlled-release oral dosage form.
 12. The method of claim1, wherein said particulate composition comprisesmicroparticles/microparticulates having average diameter selected fromthe group consisting of from 100 μm to about 150 μm; from about 150 μmto about 200 μm; from about 200 μm to about 250 μm; from about 250 μm toabout 300 μm; from about 300 μm to about 350 μm; from about 350 μm toabout 400 μm; from about 400 μm to about 450 μm; from about 450 μm toabout 500 μm; from about 500 μm to about 550 μm; from about 550 μm toabout 600 μm; from about 600 μm to about 650 μm; from about 650 μm toabout 700 μm; from about 700 μm to about 750 μm; from about 750 μm toabout 800 μm; from about 800 μm to about 850 μm; from about 850 μm toabout 900 μm; from about 150 μm to about 200 μm; from about 200 μm toabout 250 μm; from about 250 μm to about 300 μm; from about 300 μm toabout 350 μm; from about 350 μm to about 400 μm; from about 400 μm toabout 450 μm; from about 450 μm to about 500 μm; from about 500 μm toabout 550 μm; from about 550 μm to about 600 μm; from about 600 μm toabout 650 μm; from about 650 μm to about 700 μm; from about 700 μm toabout 750 μm; from about 750 μm to about 800 μm; from about 800 μm toabout 850 μm; from about 200 μm to about 250 μm; from about 250 μm toabout 300 μm; from about 300 μm to about 350 μm; from about 350 μm toabout 400 μm; from about 400 μm to about 450 μm; from about 450 μm toabout 500 μm; from about 500 μm to about 550 μm; from about 550 μm toabout 600 μm; from about 600 μm to about 650 μm; from about 650 μm toabout 700 μm; from about 700 μm to about 750 μm; from about 750 μm toabout 800 μm; from about 250 μm to about 300 μm; from about 300 μm toabout 350 μm; from about 350 μm to about 400 μm; from about 400 μm toabout 450 μm; from about 450 μm to about 500 μm; from about 500 μm toabout 550 μm; from about 550 μm to about 600 μm; from about 600 μm toabout 650 μm; from about 650 μm to about 700 μm; from about 700 μm toabout 750 μm; from about 300 μm to about 350 μm; from to about 350 μm toabout 400 μm; from to about 400 μm to about 450 nm; from to about 450 μmto about 500 μm; from to about 350 μm to about 400 μm; from to about 400μm to about 450 μm; from to about 450 μm to about 500 μm andcombinations thereof.
 13. The method of claim 1, wherein the particulatecomposition is in the forms of capsules or tablets.
 14. The method ofclaim 1, wherein said particulate composition has a particle sizedistribution selected from the group consisting of about 60% of theparticles having a particle diameter of about 1267 μm or less; 58% ofparticles having a particle diameter of about 1055 μm or less; about 53%of particles having a particle diameter of about 949 μm or less; about52% of particles having a particle diameter of about 737 μm or less;about 50% of particles having a particle diameter of about 631 μm orless; about 47% of particles having a particle diameter of about 525 μmor less; about 37% of particles having a particle diameter of about 419μm or less; about 21% of particles having a particle diameter of about313 μm or less; and about 6% of particles having a particle diameter ofabout 207 μm or less.
 15. The method of claim 1, wherein saidparticulate composition has a particle size distribution selected fromthe group consisting of about 80% of the particles having a diameter ofabout 860 μm or less; about 77% of particles having a particle diameterof about 798 μm or less; about 75% of particles having a particlediameter of about 736 μm or less; about 69% of particles having aparticle diameter of about 674 μm or less; about 65% of particles havinga particle diameter of about 612 μm or less; about 61% of particleshaving a particle diameter of about 550 μm or less; about 52% ofparticles having a particle diameter of about 488 nm or less; about 37%of particles having a particle diameter of about 426 μm or less; about26% of particles having a particle diameter of about 364 μm or less;about 10% of particles having a particle diameter of about 302 μm orless; and about 5% of particles having a particle diameter of about 240μm or less.
 16. A method of treating pain in a patient in need thereofcomprising a step of administering to the patient sprinkles comprising aparticulate composition comprising (a) a biologically active core, saidbiologically active core comprising (i) naproxen, a pharmaceuticallyacceptable salt of said naproxen, or a combination thereof and (ii) adrug binding polymer comprising a silicified high densitymicrocrystalline cellulose composed of 98% microcrystalline celluloseand 2% colloidal silicon dioxide, wherein said naproxen, saidpharmaceutically acceptable salt of said naproxen, or said combinationthereof is in reversible association with said drug binding polymer andin a weight ratio therewith of from about 20:1 to about 1:2; and (b) acoat, said coat comprising a membrane-forming polymer, saidmembrane-forming polymer comprising ethylcellulose and surrounding saidbiologically active core, wherein the particulate composition comprisesmicroparticles/microparticulates having average diameter of from about100 μm to about 900 μm; wherein the particulate composition has adissolution rate which when measured in a type 1 dissolution basketapparatus according to U.S. Pharmacopoeia XXII in phosphate buffer at pH7.2 and at 75 r.p.m. corresponds to the following dissolution pattern(1) from 15 to 50% of the total amount of said naproxen, saidpharmaceutically acceptable salt of said naproxen, or said combinationthereof is released after 0.5 hours of measurement in said apparatus;(2) from 25 to 75% of the total amount of said naproxen, saidpharmaceutically acceptable salt of said naproxen, or said combinationthereof is released after 1 hour of measurement in said apparatus; and(3) not less than 65% of the total amount of said naproxen, saidpharmaceutically acceptable salt of said naproxen, or said combinationthereof is released after 4 hours of measurement in said apparatus. 17.The method of claim 16, wherein the sprinkles are administered to thepatient together with soft food.
 18. A method of treating painassociated with a disease selected from the group consisting ofrheumatoid arthritis and osteoarthritis in a patient in need thereof,the method comprising a step of administering to the patient aparticulate composition comprising (a) a biologically active core, saidbiologically active core comprising (i) naproxen, a pharmaceuticallyacceptable salt of said naproxen, or a combination thereof and (ii) asilicified high density microcrystalline cellulose composed of 98%microcrystalline cellulose and 2% colloidal silicon dioxide, whereinsaid naproxen, said pharmaceutically acceptable salt of said naproxen,or said combination thereof is in reversible association with saidsilicified high density microcrystalline cellulose and in a weight ratiotherewith of from about 20:1 to about 1:2; and (b) a coat, said coatcomprising a membrane-forming polymer, said membrane-forming polymercomprising ethylcellulose and surrounding said biologically active core,wherein the particulate composition comprisesmicroparticles/microparticulates having average diameter of from about100 μm to about 900 μm; wherein the particulate composition has adissolution rate which when measured in a type 1 dissolution basketapparatus according to U.S. Pharmacopoeia XXII in phosphate buffer at pH7.2 and at 75 r.p.m. corresponds to the following dissolution pattern(1) from 15 to 50% of the total amount of said naproxen, saidpharmaceutically acceptable salt of said naproxen, or said combinationthereof is released after 0.5 hours of measurement in said apparatus;(2) from 25 to 75% of the total amount of said naproxen, saidpharmaceutically acceptable salt of said naproxen, or said combinationthereof is released after 1 hour of measurement in said apparatus; and(3) not less than 65% of the total amount of said naproxen, saidpharmaceutically acceptable salt of said naproxen, or said combinationthereof is released after 4 hours of measurement in said apparatus. 19.The method of claim 18, wherein the particulate composition areadministered to the patient together with soft food.
 20. The method ofclaim 18, wherein the patient has difficulty swallowing solids.